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HEMATOPOIESIS
From the Department of Internal Medicine and Molecular
Science, Graduate School of Medicine, Osaka University, Osaka, Japan,
and the Department of Molecular Biology and Biochemistry, University of
California Irvine, Irvine, CA.
We investigated the functions of adiponectin, an adipocyte-specific
secretory protein and a new member of the family of soluble defense
collagens, in hematopoiesis and immune responses. Adiponectin suppressed colony formation from colony-forming units
(CFU) Hematopoietic cell formation is regulated by
features of the bone marrow (BM) microenvironment, including cytokines,
extracellular matrix components, and stromal cells.1-3
Several cytokines that regulate proliferation and differentiation of
hematopoietic cells have been identified. Complex cell-cell or
cell-matrix interactions are also important for development of
hematopoietic stem/progenitor cells.4-7
There are several types of BM stromal cells, including mononuclear
phagocytic cells, fibroblasts, endothelial cells, and fat-containing cells. Among these, adipocytes are one of the principal cellular elements in the BM microenvironment and produce a variety of proteins that act on hematopoiesis and metabolism.8 For example,
leptin, which is the product of the obese gene and produced
primarily by adipocytes, not only regulates nutrient intake and
metabolism but augments the proliferation of myelocytic and primitive
hematopoietic progenitor cells.9-12 In addition,
adipogenesis alters the expression of the extracellular matrix,
membrane proteins, and cytokines in BM stroma. For example, the
expression of tenascin, a cytoadhesive extracellular component,
decreases during adipocyte differentiation, whereas that of hyaluronan
increases.13-16 In the production of collagens, a switch
from fibrillar (type I and III) to basement membrane (type IV)
collagens occurs along with adipocyte
differentiation.17,18 The expression of macrophage
colony-stimulating factor (M-CSF), one of the indispensable cytokines
in hematopoiesis, is decreased in stromal adipocytes relative to
preadipocytes.19,20 Thus, adipocytes are considered to
influence hematopoiesis both directly and indirectly.
We previously isolated adiponectin as an adipocyte-specific secretory
protein.21 The production of adiponectin increases in
accordance with the differentiation of preadipocytes to
adipocytes.22 Adiponectin is composed of 244 amino acid
residues containing a short noncollagenous N-terminal segment followed
by a collagen-like sequence (Figure 1).
On the basis of structural analyses of its murine homolog
Acrp30/AdipoQ,23 adiponectin is presumed to form a
homotrimeric subunit with a collagen-like triple-helical structure and
circulate through the body as a multimer of trimers. These structural
features suggest that adiponectin belongs to a family of proteins
identified as soluble defense collagens and including complement C1q
and the collectins mannose-binding lectin (MBL), lung surfactant
protein A (SP-A), lung surfactant protein D, and conglutinin (Figure
1). The collectins play important roles in the innate humoral immune
system.24-27 These proteins can identify foreign pathogens
by detecting specific carbohydrate structures uniquely present on
microorganisms, and they subsequently interact with phagocytic cells or
the complement system to bring about killing and clearance of targets
without involvement of antibodies. Lack or low levels of collectin
expression cause increased susceptibility to infections, especially in
infants, whose specific immune systems for various pathogens have not
fully developed.28
We here describe unique functions of adiponectin in hematopoiesis and
immune responses. Adiponectin serves as a negative regulator for
myelomonocytic progenitor growth. In addition, adiponectin significantly inhibits functions of mature macrophages. Our data suggest that adiponectin may be involved in preventing excessive and
prolonged inflammatory responses.
Reagents and antibodies
Source of cells
Normal human BM was aspirated from the posterior iliac crest of healthy young volunteers after informed consent was obtained. Low-density BM mononuclear cells (BMMNC) were isolated by Ficoll-Hypaque density gradient centrifugation. To enrich the CD34+ cell population, BMMNC were negative-selected by using immunomagnetic beads conjugated with anti-CD3 and anti-CD11b MoAbs and then positive-selected by using immunomagnetic beads conjugated with an antihuman CD34 MoAb (Miltenyi Biotec, Berguisch, Gladbach, Germany) as described previously.5 In our series, more than 96% of the purified cells always expressed CD34 and more than 98% were viable. Human monocyte-derived macrophages were isolated as described previously.32 Briefly, mononuclear cells were isolated from freshly collected buffy-coat preparations of whole human blood by Ficoll-Hypaque gradient centrifugation, and the cells were seeded in 24-well plastic plates (2 × 106 cells/well) or in 10-cm plastic tissue-culture dishes (2 × 107 cells/dish). The seeded cells were allowed to adhere for 1 hour in a humidified atmosphere at 37°C and 5% carbon dioxide (CO2), and nonadherent cells were removed by 3 washes with RPMI-1640 medium. The adherent cells, which were mainly monocytes, were grown in RPMI-1640 medium supplemented with 10% human type AB serum, with changing of the medium every 3 days. After incubation for 7 days, mature macrophages were obtained and used for subsequent experiments. Assays of colony formation To assess the colony formation of hematopoietic progenitor cells, serum-free methylcellulose progenitor assays were performed by using a modification of the technique described previously.33 Briefly, human BMMNC and CD34+ cells were plated at a density of 5 × 104/mL and 5 × 102/mL, respectively, in serum-free methylcellulose medium (Veritas, Vancouver, Canada) consisting of Iscove modified Dulbecco medium, 0.9% methylcellulose, 10 4 mol/L 2-mercaptoethanol, 2 mmol/L
L-glutamine, 1% deionized crystallized BSA, human
transferrin, bovine insulin, 3 U/mL rh erythropoietin, 50 ng/mL rh
stem-cell factor, 10 ng/mL rh GM-CSF, 10 ng/mL rh granulocyte
colony-stimulating factor (G-CSF), 10 ng/mL rh interleukin (IL) 3, and
10 ng/mL rh IL-6 with adiponectin or HSA. Cultures were set up in
quadruplicate and incubated in a humidified atmosphere at 37°C and
5% CO2 for 16 days. Colony types and numbers were determined on days 12 to 16 of cultures by means of in situ
observations using an inverted microscope according to established
criteria34 and assessments of cytospin preparations of
individual colonies of colony-forming units granulocyte-macrophage
(CFU-GM), colony-forming unitsmacrophage (CFU-M), colony-forming
unitsgranulocyte (CFU-G), colony-forming unitsmixed
erythroid-myeloid (CFU-mixed), and burst-forming
unitserythroid (BFU-E).
In some experiments, CD34+ cells were sorted singly into 96-well flat-bottomed microtiter plates with a fluorescence-activated cell-sorter scanner (FACScan) equipped with an automatic cell-deposition unit (Vantage; Becton Dickinson). In each well, the sorted cells were cultured in serum-free methylcellulose culture medium supplemented with 10 µg/mL adiponectin or HSA. Colony formation in each well was examined after 14 days of culture. To evaluate precisely the effects of adiponectin on colony formation from myeloid progenitor cells, CFU-GM, CFU-M, and CFU-G colony formation from 1 × 105 BMMNC was assessed in methylcellulose culture containing 30% FCS with, respectively, rh GM-CSF alone (10 ng/mL), rh M-CSF alone (100 U/mL), and rh G-CSF alone (10 ng/mL). Colony types were verified by microscopical observation of cytospin preparations from individual colonies stained with May-Grünwald-Giemsa stain. Assays of cell proliferation To quantitate proliferation of cells, a tritium-thymidine incorporation assay was used as described previously.4 Triplicate aliquots of cells (1 × 104/well) were cultured in 96-well flat-bottomed microtiter plates with 10 µg/mL HSA or adiponectin. Twenty-four hours after the initiation of culture, each well was pulsed for 4 hours with 0.0185 MBq tritium-thymidine. The cells were then harvested with a semiautomatic cell harvester (Pharmacia, Piscataway, NJ), and the incorporation was measured with a liquid scintillation counter.Apoptosis assay Nuclear DNA content was analyzed by flow cytometry as described previously.35 M1 cells were incubated with HSA or adiponectin for various times. Subsequently, the cells were fixed in cold ethanol and incubated at 20°C overnight. After centrifugation, the cells were resuspended in 300 µL propidium iodide (PI) solution containing 0.1% sodium citrate, 0.3% NP-40, 100 µg/mL RNase A, and
50 µg/mL PI and incubated in the dark at 37°C for 30 minutes. The
fluorescence emitted from the PI-DNA complex was then quantitated with
a FACScan (Becton Dickinson).
Fragmentation of DNA was analyzed as described previously.35 After incubation with HSA or adiponectin, cells were lysed in 0.4 mL lysis solution containing 200 mmol/L Tris-hydrochloric acid (HCl), 100 mmol/L EDTA, 1% sodium dodecyl sulfate, and 50 µg/mL proteinase K and incubated for 4 hours at 37°C. DNAs were extracted with phenol and then chloroform-isoamylalcohol. The aqueous phase was collected and precipitated with sodium chloride and ethanol. The ethanol-precipitated DNA was dried and resuspended in TE buffer (10 mmol/L Tris-HCl and 1 mmol/L EDTA) and treated with 50 µg/mL DNase-free RNase for 5 hours at 37°C and then with 300 µg/mL proteinase K for 5 hours at 37°C. DNAs were extracted twice and precipitated as described above. DNA pellets were resuspended in TE buffer, separated by electrophoresis in 1% agarose gel containing 0.5 µg/mL ethidium bromide (5 µg DNA per lane), and visualized under ultraviolet light. Northern blot analysis Total RNAs were isolated by using Trizol reagent (Gibco), electrophoresed through formaldehyde agarose gels (15 µg total RNA per lane), and transferred to nylon membranes (Amersham, Arlington Heights, IL). The cDNA fragments were labeled with phosphorus 32-deoxycytidine triphosphate using a random primed DNA labeling kit (Boehringer Mannheim) and hybridized to the membranes. Blots were then washed and autoradiographed. Fragments of the human Bcl-2, murine Bcl-xL, murine Bax, murine Bak, murine p53, murine -actin, human tumor necrosis
factor- (TNF-), human IL-1, and human IL-6 genes and the
B gene isolated from Chinese hamster ovary cells (a gift
from Dr Toshio Hirano, Osaka University, Osaka, Japan) were used as
materials for probes.35,36
Phagocytosis assay Phagocytosis of human macrophages was evaluated with our previously described ingestion assays for adherent cells.32 Human macrophages were preincubated in 24-well flat-bottomed plates for 24 hours at 37°C in 500 µL serum-free conditioned RPMI-1640 medium with 10 µg/mL adiponectin, HSA, or medium alone. Fluorebrite fluorescent-microspheres (0.75YG; Polyscience, Warrington, PA) solution (50 µL 0.25% solids-latex in RPMI-1640 medium) was added to each well, and incubation allowed to proceed for 1 hour at 37°C. Nonadherent latex beads were removed by washing, and the cells were incubated for 30 minutes to obtain complete phagocytosis. Cells were then harvested by short-time treatment with EDTA and trypsin and washed vigorously 3 times with phosphate-buffered saline (PBS) to remove noningested beads. Subsequently, the amount of ingested beads was measured with a FACScan.TNF- from macrophages was determined by a
heterologous 2-site sandwich enzyme-linked immunosorbent assay (ELISA) as described by Soell et al.37 First, 96-well microtiter
plates were coated with 50 µL (10 µg/mL) rabbit anti-rh TNF-
IgG. After overnight incubation at 4°C, the plates were washed with
PBS containing 0.05% Tween 20 and blocked with the same buffer
containing 0.5% gelatin for 1 hour at 37°C. Macrophage supernatants
(50 µL) were then added to the wells (2 hours at 37°C), and bound
TNF- was detected with biotinylated anti-rh TNF- IgG (2 hours at
37°C). This was followed by incubation with alkaline
phosphatase-labeled streptavidin (1 hour at 37°C) and the enzyme
substrate. After 1 hour at 25°C, the plates were read at 405 nm. The
readings were related to standard curves with rh TNF-. The
sensitivity of this ELISA was 20 pg/mL.
Adiponectin inhibits proliferation of myelomonocytic progenitor cells Our ELISA system previously revealed that adiponectin levels in plasma from healthy humans range from 1.9 to 17.0 µg/mL.29 Serum-free methylcellulose colony assays of human BMMNC were used to evaluate the influence of physiologic concentrations of adiponectin on hematopoiesis. First, we found that adiponectin reduced the number of CFU-GM colonies in a dose-dependent manner (Figure 2A). The number of CFU-GM colonies was decreased approximately 33% by the addition of 10 µg/mL rh adiponectin. The inhibitory effect was evident at 5 µg/mL and maximal at 10 to 50 µg/mL. In subsequent experiments, we used 10 µg/mL rh adiponectin. The antiadiponectin MoAb 9104, which can partly inhibit the binding of adiponectin to cells, markedly inhibited the reduction of CFU-GM formation by adiponectin, indicating that the reduction in colony formation of CFU-GM by rh adiponectin was specific (Figure 2B).
We then examined the effect of adiponectin on the colony formation of
other progenitor cells by using the same assay system (Figure
3A). CFU-M formation was also decreased
approximately 50%. However, rh adiponectin had no influence on colony
formation of BFU-E or CFU-mixed, indicating that the inhibitory effect
was highly specific for myelomonocytic progenitor cells. To verify the
inhibitory effects of adiponectin on colony formation from each type of
myelomonocytic progenitor cell separately, colonies formed in the
presence of rh GM-CSF alone, rh M-CSF alone, or rh G-CSF alone, with
and without adiponectin, were examined. Colonies stimulated only with
GM-CSF were mainly CFU-GM colonies (approximately 80%), with the
remaining colonies containing only macrophages. Almost all colonies
stimulated only with M-CSF were CFU-M colonies (> 95%). Colonies
stimulated only with G-CSF were mainly CFU-G colonies (approximately
70%), with the remaining colonies containing both granulocytes and
macrophages or only macrophages. No obvious shifts in these colony
types were observed in the absence or presence of adiponectin (data not
shown). As shown in Figure 3B, CFU-GM colonies formed with GM-CSF alone
were decreased approximately 30% by 10 µg/mL adiponectin. CFU-M and
CFU-G colonies were decreased approximately 50% and 60%,
respectively, by adiponectin.
Colony formation from sorted CD34+ cells (enriched
hematopoietic progenitor cells) was also analyzed in the presence of a
combination of growth factors. Generation of CFU-GM colonies,
but not that of BFU-E or CFU-mixed colonies, was inhibited by
adiponectin (Figure 4A). This inhibitory
effect on CFU-GM colony formation also occurred with complement C1q,
which has a structure similar to that of adiponectin (Figure 4B). To
eliminate the possibility that the inhibitory effect was mediated by
accessory cells, the effect of adiponectin on CFU-GM colony formation
from singly sorted CD34+ cells was examined. As shown in
Figure 4C, CFU-GM colony formation was also significantly inhibited by
adiponectin when only a single CD34+ cell was placed in
each well.
Several lymphohematopoietic cell lines were cultured in serum-free
conditions with rh adiponectin or HSA, and their proliferation was
evaluated. In the tested myeloid cell lines, tritium-thymidine incorporation of THP1, KU812, M1, and WEHI3 cells was inhibited by
incubation with adiponectin, whereas proliferation of KG1, HL60, MO7E,
and F36p cells was not affected (Table
1). Interestingly, the numbers of
recovered viable cells were markedly decreased by adiponectin,
especially in the THP1 and M1 cell lines. In these lines, treatment
with adiponectin for 48 hours significantly increased the proportion of
dead cells (by 45.3% ± 2.7% [THP1] and 30.9% ± 8.5% [M1]).
Proliferation of the tested erythroid (K562, HEL, and F36e) and T- and
B-cell lines (MOLT4, Jurkat, CCRF-CEM, EL4, Nalm6, ONHL1, and OPM2) was
not affected by rh adiponectin, except in the case of BALL, a
pre-B-cell line (Table 1). These results show that adiponectin serves
as a negative regulator of the growth of limited cell lineages,
especially myelomonocytic progenitors.
Adiponectin induces apoptosis in acute myelomonocytic leukemia cell lines We performed experiments to analyze the mechanisms of the growth inhibition induced by adiponectin. Viable cell numbers and viability of M1 cells treated with rh adiponectin or HSA were evaluated every 24 hours (Figure 5A). Treatment with rh adiponectin strongly inhibited proliferation of M1 cells, and the cells lost their viability within 48 hours. Morphologic analysis after May-Grünwald-Giemsa staining indicated that treatment with adiponectin for 48 hours led to a distinctive condensation of chromatin and fragmented nuclei in M1 cells (Figure 5B). A subdiploid peak of DNAs appeared within 48 hours after initiation of rh adiponectin treatment and increased as treatment continued (Figure 5C). Thus, the proportions of the subdiploid population were 9.27% after 48 hours of rh adiponectin treatment and 25.35% after 72 hours, whereas the proportions with HSA were 2.64% at 48 hours and 3.55% at 72 hours. Moreover, DNA fragmentation into oligonucleosomal-sized pieces was readily visible in M1 cells after 48 hours of treatment with rh adiponectin but barely detected in M1 cells cultured with HSA (Figure 5D). These results indicate that adiponectin induced apoptosis in an acute myelomonocytic leukemia cell line, M1. Essentially the same results were observed in an acute monocytic leukemia cell line, THP1 (data not shown).
Adiponectin modulates expression of apoptosis-related genes in M1 cells, and constitutive expression of Bcl-2 suppresses adiponectin-induced apoptosis To further investigate molecular mechanisms involved in the responses of M1 cells to adiponectin, we evaluated expression of some apoptosis-related genes by using Northern blot analysis. As shown in Figure 6A, M1 cells expressed Bcl-2, Bcl-xL, and Bax genes. Expression of the Bcl-2 gene was down-regulated to an undetectable level by treatment with adiponectin for 48 hours. Expression of the Bcl-xL gene also appeared to be down-regulated by adiponectin treatment, although the initial expression level of this gene was weak. In contrast, expression of Bax was not affected by adiponectin. Neither Bak nor the p53 gene was expressed in the cells at a level detectable with Northern blot analysis, and their expression was not induced by incubation with adiponectin (data not shown). Therefore, treatment with adiponectin down-regulated the expression of antiapoptotic genes, especially Bcl-2, in M1 cells, but had no effects on expression of the apoptosis-inducing genes Bax, Bak, and p53.
Adiponectin down-regulated Bcl-2 gene expression. To evaluate the role of this change in adiponectin-induced responses, a human Bcl-2-expression plasmid, pcDNA3-hBcl-2, was stably transfected into M1 cells, and 3 individual clones that expressed human Bcl-2 under the control of a cytomegalovirus promoter (M1 hBcl-2 clone 1-3) were obtained. As controls, 3 individual transfectants with pcDNA3 alone were also established (M1 pcDNA3 clone 1-3). The amount of endogenous and exogenous Bcl-2 gene expression in each transfectant was confirmed by Northern blot analysis (Figure 6B). As shown in Figure 6C, M1 parent cells and pcDNA3 clones were severely deprived of viability by incubation with adiponectin, whereas M1 hBcl-2 clones evaded adiponectin-induced cell death. These findings indicate that Bcl-2 is sufficient to block adiponectin-induced apoptosis. Adiponectin inhibits phagocytic activity of mature macrophages We analyzed influences of adiponectin on the differentiation of monocytes to macrophages and the functions of mature macrophages. Human peripheral blood monocytes differentiate to mature macrophages when they are cultured in RPMI-1640 medium supplemented with 10% human type AB serum for 7 days. Addition of rh adiponectin to these cultures caused monocytes to have slightly rounded shapes and reduced proliferation (data not shown). However, their viability was not influenced and the cells grew to show macrophage-like morphologic features after 7 days of culture (data not shown). The viability of mature macrophages was also unaffected by treatment with adiponectin for at least 72 hours (data not shown).To evaluate the influence of adiponectin on phagocytic activity of
mature macrophages, the cells were pretreated with rh adiponectin or
HSA for 24 hours and then subjected to phagocytosis assays using
Fluorebrite fluorescent microspheres. As shown in Figure 7, treatment with adiponectin
significantly suppressed the phagocytosis of macrophages (median
fluorescence intensity, 181.67 ± 14.57 with rh adiponectin and
486.58 ± 32.11 with HSA).
Adiponectin inhibits lipopolysaccharide (LPS)-induced TNF- mRNA was markedly suppressed by pretreatment with
rh adiponectin, whereas induction of IL-1 and IL-6 mRNA expression was not affected. The inhibitory effect of adiponectin on LPS-induced TNF- production was also confirmed by assessment of secreted protein
levels in the supernatants. Adiponectin-treated macrophages failed to
release TNF- in response to LPS (Table
2). When the kinetics of this inhibition
was analyzed, we found that TNF- mRNAs were strongly induced within
2 hours and detected for 8 hours when macrophages were stimulated by
LPS (Figure 8B). However, no messages were detected during the
observation periods when macrophages were pretreated with rh
adiponectin for 24 hours. As shown in Figure 8C, adiponectin barely
inhibited LPS-induced TNF- expression of macrophages when it was
added at the time of LPS stimulation (pretreatment time 0 hour).
However, LPS-induced TNF- gene expression was obviously reduced by
pretreatment with rh adiponectin for 1 hour. In addition, longer
pretreatment with rh adiponectin resulted in stronger suppression of
TNF- gene induction.
C1qRp is one of the cell-surface receptors for adiponectin Adiponectin and complement C1q have a substantial sequence similarity. C1qRp is one of the receptors for C1q on phagocytic cells.30,31 To clarify whether the functions of adiponectin might be mediated by C1qRp, we examined the effect of R3, a murine MoAb blocking C1qRp, on those functions. As shown in Figure 9A, MoAb R3 completely abrogated the suppression of phagocytosis of macrophages by adiponectin. However, MoAb R3 did not affect the suppression of TNF- transcription by
adiponectin (Figure 9B). In addition, neither the reduction of CFU-GM
and CFU-M formation nor the inhibition of growth in myelomonocytic cell
lines by adiponectin was canceled by MoAb R3 (data not shown). These
results suggest that C1qRp is one of the receptors for adiponectin and
mediates its inhibitory effect on macrophage phagocytosis.
Adiponectin, an adipocyte-derived secretory protein, is a new member of the family of proteins that includes C1q and the collectins. The proteins in this family contain both collagen-like and noncollagen domains. In this study, we observed novel functions of adiponectin in hematopoiesis and immune responses. Adiponectin predominantly suppressed proliferation of myelomonocytic progenitors. It also inhibited mature macrophage functions, such as phagocytosis and cytokine production. These results suggest that adiponectin is an important regulator of inflammatory responses. Adiponectin suppressed the colony formation of CFU-GM, CFU-M, and CFU-G, but had little or no effect on that of BFU-E and CFU-mixed. The suppression was unlikely to have been mediated by accessory cells because CFU-GM colony formation from single, isolated CD34+ cells was also inhibited by adiponectin. In addition, cell growth in 4 of 9 myeloid cell lines but not in erythroid or lymphoid cell lines other than the BALL cell line was inhibited by adiponectin. Thus, the growth inhibitory effects of adiponectin were apparent mainly in cells of myelomonocytic lineage. The experiments using myeloid cell lines showed that growth inhibition by adiponectin was at least partly mediated by induction of apoptosis. Furthermore, down-regulation of Bcl-2 expression was shown to play a role in induction of apoptosis by adiponectin. However, induction of apoptosis was not obvious in CD34+ cells treated with adiponectin (data not shown). Several cytokines, such as TNFs, interferons, and transforming growth factors (TGFs), have the capacity to inhibit hematopoiesis,38 and these cytokines have been shown to suppress proliferation of a wide range of lymphohematopoietic progenitors. In contrast, target cells for adiponectin are restricted to myelomonocytic lineage committed progenitors. Macrophages play a central role in immune responses by means of
secretion of inflammatory cytokines, phagocytic activity, and antigen
presentation.39 Our results show that adiponectin inhibits
phagocytosis and LPS-induced TNF- Among the physiologic substances associated with inflammation, E-type
prostaglandins (PGE) were shown to inhibit colony formation from CFU-GM
and CFU-M but not that from BFU-E.44 Furthermore, PGE2 was reported to inhibit TNF- Members of the soluble defense collagen family, including C1q and the
collectins, have similar structures and functions.24-27 They can identify foreign pathogens and subsequently interact with
phagocytic cells and complement to bring about killing and clearance of
targets. Here, we found new functions of adiponectin. MBL and SP-A were
shown previously to reduce TNF- Adiponectin and complement C1q have a marked sequence similarity. C1q
interacts with a variety of cell-surface receptors.30,52 Although most C1q receptors have not yet been found to mediate cellular
responses, C1qRp is known to enhance phagocytosis through binding to
C1q.30 Interestingly, MBL and SP-A are also recognized by
C1qRp.49,50 We conclude that adiponectin also modulates phagocytic activity of macrophages through C1qRp because we found that
MoAb R3 completely blocked suppression of phagocytosis by adiponectin.
However, the mechanism by which C1qRp mediates contrary functions on
phagocytosis remains to be elucidated. It is possible that the
functional receptor for regulating phagocytosis is a multisubunit
complex including C1qRp, as previously speculated.30 Adiponectin and C1q might use different associated molecules to transduce their signals into phagocytic cells. The lack of inhibition by MoAb R3 of the suppressive effects of adiponectin on the growth of
myelomonocytic progenitors and the TNF- Adiponectin is a plasma protein secreted exclusively from adipocytes. In plasma from healthy humans, it exists in concentrations ranging from 1.9 to 17.0 µg/mL. However, it remains unclear whether all in vivo adiponectin have the same activities. Although direct proof is lacking, some speculations about the in vivo status of adiponectin may be made on the basis of the fact that C1q is also a plasma protein and its structure is very similar to that of adiponectin. The cell-interaction site of C1q is located in a region that is normally masked in C1 component and becomes exposed as a result of dissociation of activated C1r2C1s2 components on binding to immune complexes or other ligands.53 A similar situation might exist in the mechanism of adiponectin activation. Adiponectin seems to be set up in vivo for immediate modification of immoderate inflammatory reactions occurring after invasion by foreign pathogens. On the other hand, C1q is thought to play a critical in vivo role in restraining autoimmunity by clearing apoptotic cells that provide the source of autoantigens.54,55 C1q-deficient mice have high titers of antinuclear antibodies and glomerulonephritis with multiple apoptotic cell bodies.55 In this case, part of adiponectin might constitutively function in vivo to maintain a homeostatic state in hematopoiesis and immune systems. In any case, adiponectin is quite different from other immune regulatory cytokines because they are barely produced until stimuli such as infections activate their secretory cells. Adiponectin is likely to regulate inflammatory responses negatively
through at least 2 mechanisms: suppression of mature macrophage functions and inhibition of growth of macrophage precursors. The former
is considered to play an important role in the control of early
responses of inflammation, and the latter may act in late events of
inflammation to prevent immune responses from continuing chronically.
All the data described here indicate that adiponectin is involved in
the termination of inflammatory responses. Of course, the inflammatory
responses to eliminate invasive foreign pathogens are important for
host defense, but the systems to prevent those responses from spreading
and persisting immoderately are also indispensable. TNF-
We thank Dr Masahiro Muraguchi (Otuka Pharmaceutical Co Ltd, Tokushima, Japan) for excellent technical support.
Submitted November 23, 1999; accepted May 1, 2000.
Supported in part by grants from the Ministry of Education, Science and Culture of Japan; the Japan Society for the Promotion of Science; and the Yamanouchi Foundation for Research on Metabolic Disorders.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Takafumi Yokota, Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan; e-mail: yokota{at}imed2.med.osaka-u.ac.jp.
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 H. Motoshima, B. J. Goldstein, M. Igata, and E. Araki AMPK and cell proliferation - AMPK as a therapeutic target for atherosclerosis and cancer J. Physiol., July 1, 2006; 574(1): 63 - 71. [Abstract] [Full Text] [PDF]
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A M Lorincz and S Sukumar Molecular links between obesity and breast cancer. Endocr. Relat. Cancer, June 1, 2006; 13(2): 279 - 292. [Abstract] [Full Text] [PDF]
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 M. Nishimura, T. Hashimoto, H. Kobayashi, S. Yamazaki, K. Okino, H. Fujita, N. Inoue, H. Takahashi, and T. Ono Association of the circulating adiponectin concentration with coronary in-stent restenosis in haemodialysis patients Nephrol. Dial. Transplant., June 1, 2006; 21(6): 1640 - 1647. [Abstract] [Full Text] [PDF]
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K.-y. Kim, J. K. Kim, S. H. Han, J.-S. Lim, K. I. Kim, D. H. Cho, M.-S. Lee, J.-H. Lee, D.-Y. Yoon, S. R. Yoon, et al. Adiponectin Is a Negative Regulator of NK Cell Cytotoxicity J. Immunol., May 15, 2006; 176(10): 5958 - 5964. [Abstract] [Full Text] [PDF]
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M. Neumeier, J. Weigert, A. Schaffler, G. Wehrwein, U. Muller-Ladner, J. Scholmerich, C. Wrede, and C. Buechler Different effects of adiponectin isoforms in human monocytic cells J. Leukoc. Biol., April 1, 2006; 79(4): 803 - 808. [Abstract] [Full Text] [PDF]
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K. Matsushita, H. Yatsuya, K. Tamakoshi, K. Wada, R. Otsuka, S. Takefuji, K. Sugiura, T. Kondo, T. Murohara, and H. Toyoshima Comparison of Circulating Adiponectin and Proinflammatory Markers Regarding Their Association With Metabolic Syndrome in Japanese Men Arterioscler Thromb Vasc Biol, April 1, 2006; 26(4): 871 - 876. [Abstract] [Full Text] [PDF]
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S. K. Jacobi, N. K. Gabler, K. M. Ajuwon, J. E. Davis, and M. E. Spurlock Adipocytes, myofibers, and cytokine biology: New horizons in the regulation of growth and body composition J Anim Sci, April 1, 2006; 84(13_suppl): E140 - E. [Abstract] [Full Text] [PDF]
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M. Mohlig, M. Freudenberg, T. Bobbert, M. Ristow, H. Rochlitz, M. O. Weickert, A. F. H. Pfeiffer, and J. Spranger Acetylsalicylic Acid Improves Lipid-Induced Insulin Resistance in Healthy Men J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 964 - 967. [Abstract] [Full Text] [PDF]
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S. Lee, F. Bacha, N. Gungor, and S. A. Arslanian Racial Differences in Adiponectin in Youth: Relationship to visceral fat and insulin sensitivityv Diabetes Care, January 1, 2006; 29(1): 51 - 56. [Abstract] [Full Text] [PDF]
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C. G. Schalkwijk, N. Chaturvedi, M. T. Schram, J. H. Fuller, C. D. A. Stehouwer, and the EURODIAB Prospective Complications Study Group Adiponectin Is Inversely Associated with Renal Function in Type 1 Diabetic Patients J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 129 - 135. [Abstract] [Full Text] [PDF]
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H. Kato, H. Kashiwagi, M. Shiraga, S. Tadokoro, T. Kamae, H. Ujiie, S. Honda, S. Miyata, Y. Ijiri, J. Yamamoto, et al. Adiponectin Acts as an Endogenous Antithrombotic Factor Arterioscler Thromb Vasc Biol, January 1, 2006; 26(1): 224 - 230. [Abstract] [Full Text] [PDF]
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C. Kobashi, M. Urakaze, M. Kishida, E. Kibayashi, H. Kobayashi, S. Kihara, T. Funahashi, M. Takata, R. Temaru, A. Sato, et al. Adiponectin Inhibits Endothelial Synthesis of Interleukin-8 Circ. Res., December 9, 2005; 97(12): 1245 - 1252. [Abstract] [Full Text] [PDF]
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 Y. Takemura, Y. Osuga, M. Harada, T. Hirata, K. Koga, C. Morimoto, Y. Hirota, O. Yoshino, T. Yano, and Y. Taketani Serum adiponectin concentrations are decreased in women with endometriosis Hum. Reprod., December 1, 2005; 20(12): 3510 - 3513. [Abstract] [Full Text] [PDF]
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 E. K. Wei, E. Giovannucci, C. S. Fuchs, W. C. Willett, and C. S. Mantzoros Low Plasma Adiponectin Levels and Risk of Colorectal Cancer in Men: A Prospective Study J Natl Cancer Inst, November 16, 2005; 97(22): 1688 - 1694. [Abstract] [Full Text] [PDF]
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 P. O. Iversen and H. Wiig Tumor Necrosis Factor {alpha} and Adiponectin in Bone Marrow Interstitial Fluid from Patients with Acute Myeloid Leukemia Inhibit Normal Hematopoiesis Clin. Cancer Res., October 1, 2005; 11(19): 6793 - 6799. [Abstract] [Full Text] [PDF]
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T. Bobbert, H. Rochlitz, U. Wegewitz, S. Akpulat, K. Mai, M. O. Weickert, M. Mohlig, A. F.H. Pfeiffer, and J. Spranger Changes of Adiponectin Oligomer Composition by Moderate Weight Reduction Diabetes, September 1, 2005; 54(9): 2712 - 2719. [Abstract] [Full Text] [PDF]
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C. S. Mantzoros, T. Li, J. E. Manson, J. B. Meigs, and F. B. Hu Circulating Adiponectin Levels Are Associated with Better Glycemic Control, More Favorable Lipid Profile, and Reduced Inflammation in Women with Type 2 Diabetes J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4542 - 4548. [Abstract] [Full Text] [PDF]
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L. J. Martin, J. G. Woo, S. R. Daniels, E. Goodman, and L. M. Dolan The Relationships of Adiponectin with Insulin and Lipids Are Strengthened with Increasing Adiposity J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 4255 - 4259. [Abstract] [Full Text] [PDF]
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M. Bullo, M. R. Peeraully, and P. Trayhurn Stimulation of NGF expression and secretion in 3T3-L1 adipocytes by prostaglandins PGD2, PGJ2, and {Delta}12-PGJ2 Am J Physiol Endocrinol Metab, July 1, 2005; 289(1): E62 - E67. [Abstract] [Full Text] [PDF]
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K Yamamoto, T Kiyohara, Y Murayama, S Kihara, Y Okamoto, T Funahashi, T Ito, R Nezu, S Tsutsui, J-I Miyagawa, et al. Production of adiponectin, an anti-inflammatory protein, in mesenteric adipose tissue in Crohn's disease Gut, June 1, 2005; 54(6): 789 - 796. [Abstract] [Full Text] [PDF]
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S. Otake, H. Takeda, Y. Suzuki, T. Fukui, S. Watanabe, K. Ishihama, T. Saito, H. Togashi, T. Nakamura, Y. Matsuzawa, et al. Association of Visceral Fat Accumulation and Plasma Adiponectin with Colorectal Adenoma: Evidence for Participation of Insulin Resistance Clin. Cancer Res., May 15, 2005; 11(10): 3642 - 3646. [Abstract] [Full Text] [PDF]
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Y. Wang, K. S. L. Lam, J. Y. Xu, G. Lu, L. Y. Xu, G. J. S. Cooper, and A. Xu Adiponectin Inhibits Cell Proliferation by Interacting with Several Growth Factors in an Oligomerization-dependent Manner J. Biol. Chem., May 6, 2005; 280(18): 18341 - 18347. [Abstract] [Full Text] [PDF]
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 K. M. Ajuwon and M. E. Spurlock Adiponectin inhibits LPS-induced NF-{kappa}B activation and IL-6 production and increases PPAR{gamma}2 expression in adipocytes Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2005; 288(5): R1220 - R1225. [Abstract] [Full Text] [PDF]
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B. Wang, J. R. Jenkins, and P. Trayhurn Expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture: integrated response to TNF-{alpha} Am J Physiol Endocrinol Metab, April 1, 2005; 288(4): E731 - E740. [Abstract] [Full Text] [PDF]
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 J.-M. Fernandez-Real, J. Vendrell, and W. Ricart Circulating Adiponectin and Plasma Fatty Acid Profile Clin. Chem., March 1, 2005; 51(3): 603 - 609. [Abstract] [Full Text] [PDF]
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A M Diehl, Z P Li, H Z Lin, and S Q Yang Cytokines and the pathogenesis of non-alcoholic steatohepatitis Gut, February 1, 2005; 54(2): 303 - 306. [Full Text] [PDF]
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M. B. Schulze, I. Shai, E. B. Rimm, T. Li, N. Rifai, and F. B. Hu Adiponectin and Future Coronary Heart Disease Events Among Men With Type 2 Diabetes Diabetes, February 1, 2005; 54(2): 534 - 539. [Abstract] [Full Text] [PDF]
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H. Waki, T. Yamauchi, J. Kamon, S. Kita, Y. Ito, Y. Hada, S. Uchida, A. Tsuchida, S. Takekawa, and T. Kadowaki Generation of Globular Fragment of Adiponectin by Leukocyte Elastase Secreted by Monocytic Cell Line THP-1 Endocrinology, February 1, 2005; 146(2): 790 - 796. [Abstract] [Full Text] [PDF]
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C. J. G. de Almeida, L. B. Chiarini, J. P. da Silva, P. M. R. e Silva, M. A. Martins, and R. Linden The cellular prion protein modulates phagocytosis and inflammatory response J. Leukoc. Biol., February 1, 2005; 77(2): 238 - 246. [Abstract] [Full Text] [PDF]
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M. Ishikawa, J. Kitayama, S. Kazama, T. Hiramatsu, K. Hatano, and H. Nagawa Plasma Adiponectin and Gastric Cancer Clin. Cancer Res., January 15, 2005; 11(2): 466 - 472. [Abstract] [Full Text] [PDF]
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C. Pagano, G. Soardo, W. Esposito, F. Fallo, L. Basan, D. Donnini, G. Federspil, L. A Sechi, and R. Vettor Plasma adiponectin is decreased in nonalcoholic fatty liver disease Eur. J. Endocrinol., January 1, 2005; 152(1): 113 - 118. [Abstract] [Full Text] [PDF]
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A. M. Delaigle, J.-C. Jonas, I. B. Bauche, O. Cornu, and S. M. Brichard Induction of Adiponectin in Skeletal Muscle by Inflammatory Cytokines: in Vivo and in Vitro Studies Endocrinology, December 1, 2004; 145(12): 5589 - 5597. [Abstract] [Full Text] [PDF]
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A. H. Berg, Y. Lin, M. P. Lisanti, and P. E. Scherer Adipocyte differentiation induces dynamic changes in NF-{kappa}B expression and activity Am J Physiol Endocrinol Metab, December 1, 2004; 287(6): E1178 - E1188. [Abstract] [Full Text] [PDF]
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G. K. Shetty, P. A. Economides, E. S. Horton, C. S. Mantzoros, and A. Veves Circulating Adiponectin and Resistin Levels in Relation to Metabolic Factors, Inflammatory Markers, and Vascular Reactivity in Diabetic Patients and Subjects at Risk for Diabetes Diabetes Care, October 1, 2004; 27(10): 2450 - 2457. [Abstract] [Full Text] [PDF]
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J. Malyszko, J. S. Malyszko, S. Brzosko, S. Wolczynski, and M. Mysliwiec Adiponectin Is Related to CD146, a Novel Marker of Endothelial Cell Activation/Injury in Chronic Renal Failure and Peritoneally Dialyzed Patients J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4620 - 4627. [Abstract] [Full Text] [PDF]
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M. B. Schulze, E. B. Rimm, I. Shai, N. Rifai, and F. B. Hu Relationship Between Adiponectin and Glycemic Control, Blood Lipids, and Inflammatory Markers in Men With Type 2 Diabetes Diabetes Care, July 1, 2004; 27(7): 1680 - 1687. [Abstract] [Full Text] [PDF]
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B. J. Goldstein and R. Scalia Adiponectin: A Novel Adipokine Linking Adipocytes and Vascular Function J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2563 - 2568. [Abstract] [Full Text] [PDF]
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 Y Nakamura, K Shimada, D Fukuda, Y Shimada, S Ehara, M Hirose, T Kataoka, K Kamimori, S Shimodozono, Y Kobayashi, et al. Implications of plasma concentrations of adiponectin in patients with coronary artery disease Heart, May 1, 2004; 90(5): 528 - 533. [Abstract] [Full Text] [PDF]
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 T. Pischon, C. J. Girman, G. S. Hotamisligil, N. Rifai, F. B. Hu, and E. B. Rimm Plasma Adiponectin Levels and Risk of Myocardial Infarction in Men JAMA, April 14, 2004; 291(14): 1730 - 1737. [Abstract] [Full Text] [PDF]
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K. Ohashi, N. Ouchi, S. Kihara, T. Funahashi, T. Nakamura, S. Sumitsuji, T. Kawamoto, S. Matsumoto, H. Nagaretani, M. Kumada, et al. Adiponectin I164T mutation is associated with the metabolic syndrome and coronary artery disease J. Am. Coll. Cardiol., April 7, 2004; 43(7): 1195 - 1200. [Abstract] [Full Text] [PDF]
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J.-M. Fernandez-Real, A. Castro, G. Vazquez, R. Casamitjana, A. Lopez-Bermejo, G. Penarroja, and W. Ricart Adiponectin Is Associated With Vascular Function Independent of Insulin Sensitivity Diabetes Care, March 1, 2004; 27(3): 739 - 745. [Abstract] [Full Text] [PDF]
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A. G. Pittas, N. A. Joseph, and A. S. Greenberg Adipocytokines and Insulin Resistance J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 447 - 452. [Full Text] [PDF]
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H. Bays, L. Mandarino, and R. A. DeFronzo Role of the Adipocyte, Free Fatty Acids, and Ectopic Fat in Pathogenesis of Type 2 Diabetes Mellitus: Peroxisomal Proliferator-Activated Receptor Agonists Provide a Rational Therapeutic Approach J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 463 - 478. [Full Text] [PDF]
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M. Garaulet, N. Viguerie, S. Porubsky, E. Klimcakova, K. Clement, D. Langin, and V. Stich Adiponectin Gene Expression and Plasma Values in Obese Women during Very-Low-Calorie Diet. Relationship with Cardiovascular Risk Factors and Insulin Resistance J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 756 - 760. [Abstract] [Full Text] [PDF]
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A. Sierksma, H. Patel, N. Ouchi, S. Kihara, T. Funahashi, R. J. Heine, D. E. Grobbee, C. Kluft, and H. F.J. Hendriks Effect of Moderate Alcohol Consumption on Adiponectin, Tumor Necrosis Factor-{alpha}, and Insulin Sensitivity Diabetes Care, January 1, 2004; 27(1): 184 - 189. [Abstract] [Full Text] [PDF]
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E. Sivan, S. Mazaki-Tovi, C. Pariente, Y. Efraty, E. Schiff, R. Hemi, and H. Kanety Adiponectin in Human Cord Blood: Relation to Fetal Birth Weight and Gender J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5656 - 5660. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
