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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 11 (June 1), 1998:
pp. 4242-4247
Characterization of a Novel CC Chemokine, HCC-4, Whose Expression
Is Increased by Interleukin-10
By
Joseph A. Hedrick,
Allison Helms,
Alain Vicari, and
Albert Zlotnik
From DNAX Research Institute, Palo Alto, CA.
 |
ABSTRACT |
We have identified and characterized a human  (CC) chemokine,
designated HCC-4, that is most closely related to HCC-1 and which
demonstrates chemotactic activity for monocytes. Northern analysis of
multiple tissue blots and of activated monocytes mRNA shows expression
of a 500-bp mRNA. A 1,500-bp mRNA was highly expressed in monocytes
activated 12 hours in the presence of interleukin-10 (IL-10) but was
absent in monocytes activated for only 1 hour regardless of the
presence or absence of IL-10. The upregulation of expression in the
presence of IL-10 is in contrast to the downregulatory effects of IL-10
on expression of most other chemokines. Recombinant HCC-4 demonstrated
chemotactic activity for human monocytes and THP-1 monocyte cells but
not for resting lymphocytes or neutrophils. HCC-4 also induced a
Ca2+ flux in THP-1 cells that was desensitized by prior
exposure to RANTES. Taken together, these data indicate that HCC-4 is a
novel chemokine whose expression is uniquely upregulated by IL-10.
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INTRODUCTION |
ALTHOUGH THE BIOLOGY of interleukin-10
(IL-10) is very complex1 it has been associated with a
number of anti-inflammatory effects. The anti-inflammatory properties
of IL-10 include downregulation of adhesion and costimulatory
molecules, inhibition of NO synthesis, and the downregulation of IL-1,
IL-6, and tumor necrosis factor- (TNF-) production by
monocytes.2 IL-10 has also been shown to upregulate the
expression IL-1 receptor antagonist (IL-1ra), apparently through
stabilization of its mRNA.3
The family of small peptide cytokines known as chemokines, in contrast,
is generally associated with proinflammatory processes.4 Indeed, a characteristic biological function of the chemokines is their
ability to induce the trafficking of leukocytes into the site of an
inflammatory response.4,5 In addition to these activities,
various chemokines have been found to stimulate granule release by
basophils and eosinophils6-8 and to upregulate the expression of adhesion markers. In keeping with this concept, expression of many of the various chemokines has been found to be
upregulated by inflammatory cytokines such as IL-1, TNF-, and
interferon- (IFN-)9-12 and downregulated by the
anti-inflammatory cytokine IL-10.9,10,12-15
In contrast to the large body of work supporting the role of chemokines
in the initiation and effector phases of inflammation, there has been
very little evidence suggesting an anti-inflammatory role for
chemokines. We report here a previously uncharacterized human (CC)
chemokine that is upregulated in the presence IL-10 and that is active
on monocytes. Because this chemokine is most closely related to
HCC-116 and its uncharacterized splice variant HCC-3
(GenBank accession no. Z70293), we have designated it HCC-4.
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MATERIALS AND METHODS |
Bioinformatics.
A human expressed sequence tag (EST) with a high degree of homology to
the chemokines was identified using a chemokine consensus sequence
as the basis for a TBLASTN search of the public database of ESTs
(dbEST). Nucleic acid sequence analysis and editing was performed using
the Sequencher (Genecodes Corp, Ann Arbor, MI). Prediction of the
signal peptide cleavage site was made through the SignalP server
(http://www.cbs.dtu.dk/services/SignalP).17 The nucleotide
and protein sequences of human HCC-4 have been deposited in GenBank
under the accession no. U91746. Phylogenetic analysis was performed
using the Clustal W program.18
Nucleotide sequencing and sequence analysis.
The cDNA clone 77539 (corresponding to GenBank accession nos. T58847
and T58775, encoding HCC-4) was purchased from Research Genetics Inc
(Birmingham, AL). The nucleotide sequence of HCC-4 was then confirmed
by automated sequencing using an Applied Biosystems 373 sequencer
(Foster City, CA). The individual sequences obtained were then
assembled into a contiguous sequence (contig) using Sequencher.
Tissue distribution and cellular expression of HCC-4 mRNA.
The tissue distribution of HCC-4 mRNA was assessed by Northern blot
analysis of multiple tissue blots (Clonetech, Palo Alto, CA) and
multiple tissue dot-blots (BioChain Institute, San Leandro, CA). Blots
were hybridized with the full-length (1.5 kb) HCC-4 probe labeled with
the DIG-High Prime kit (Boehringer Mannheim, Indianapolis, IN)
according to the manufacturer's instructions and washed under high
stringency conditions (65°C, 0.2× SSC). Expression was
confirmed using a smaller probe corresponding to the coding region of
HCC-4. The expression of HCC-4 was also analyzed by Southern blot of
cDNA libraries using a 32P-labeled, full-length probe as
previously described.19 Human monocyte mRNA was obtained
from elutriated human monocytes activated with LPS (5 µg/mL) for
either 1 hour or 12 hours in the presence of recombinant human IL-10
(200 U/mL) or the neutralizing anti-IL-10 monoclonal antibody (MoAb)
19F1 (10 µg/mL). The Northern analysis of the human monocytes was
performed with the same probe used in the library blots.
Expression of recombinant HCC-4.
A DNA sequence encoding amino acids 24-120 of HCC-4 (corresponding to
the predicted mature protein) was expressed in Escherichia coli
as a fusion protein with a 30-kD leader protein. After solubilization and refolding of the inclusion bodies, the fusion protein was cleaved
with factor Xa and purified using Fast Flow S cation exchange column
chromatography followed by C4 reverse-phase
high-performance liquid chromatography (HPLC) column
chromatography. The amino-terminal sequence was confirmed by sequencing
and preparations obtained were greater than 97% pure as determined by
sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE).
Endotoxin levels were less than 0.1 ng/mg of protein.
Biological activity of recombinant HCC-4.
The biological activity of the recombinant protein was analyzed by
microchemotaxis using a 48-well Boyden chamber (Neuroprobe, Cabin John,
MD) as previously described.20 Ca2+ flux upon
chemokine stimulation was measured using indo-1-AM (Calbiochem, La
Jolla, CA) loaded THP-1 cells and a Photon Technologies spectrofluorometer (South Brunswick, NJ) with an excitation wavelength of 350 nm. Recombinant human RANTES was obtained from R&D Systems (Minneapolis, MN).
| |
RESULTS |
Identification of the human CC chemokine HCC-4 and localization to
chromosome 17.
Using a chemokine consensus sequence as the basis for a TBLASTN search
of the public EST database (dbEST) a single EST (GenBank accession no.
T58847) was identified that encoded a novel human CC chemokine. The
T58847 sequence represents the 5 end of IMAGE clone 77539, which
originated from a cDNA library of adult liver. Using this sequence as
the basis for a subsequent BLASTN search of dbEST showed no additional
overlapping sequences (ie, no additional, contiguous sequences could be
found); however, a 3 sequence (GenBank accession no.
T58775) was found by querying GenBank with the IMAGE clone number. This
3 sequence contained an AATAAA polyadenylation signal near its
end, indicating that the clone was likely to be full-length. To confirm
this, clone 77539 was obtained and sequenced in its entirety. The
results confirmed that the clone was indeed fulllength and that it
encoded a novel (CC) chemokine (Fig 1).
Interestingly, the full-length sequence was found to contain two
polyadenylation (polyA) signals as well as a potential mRNA instability
sequence (Fig 1). The first polyA signal precedes the instability
sequence, raising the possibility of two differentially regulated mRNAs
depending on which polyA site is used. Indeed, we have observed shorter cDNA clones that are identical to clone 77539, except that it terminates in a polyA tail just downstream from the first polyA signal
and lacks the putative instability sequence. The predicted amino acid
sequence obtained from the ORF of clone 77539 shows a typical chemokine sequence containing four conserved cysteines in the expected
positions (Fig 1).
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| Fig 1.
Nucleic and amino acid sequence of human HCC-4. The
putative signal peptide is underlined as are the two potential polyA
signal sequences present in the 3 UTR. An AU-rich element in the
3 UTR is indicated in bold. These sequence data have
been submitted to GenBank under the accession no. U91746.
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To determine the chromosomal localization of HCC-4, we searched the
human gene map consortium data at the National Center for Biotechnology
Information (http://www.ncbi.nlm.nih.gov/SCIENCE96/ResTools.html) using
the full-length HCC-4 cDNA sequence. This search found a single
sequence tagged site (STS; GenBank accession no. G07028) that is
identical to the last 300 bases of the 1.5-kb HCC-4 cDNA (data not
shown), including a short repeat sequence of less than 40 bases. This
STS has been mapped to a region between 58 and 65 centimorgans on
chromosome 17 by the Whitehead Institute Center for Genome Research
using a yeast artificial chromosome panel. Chromosome 17 is also known
to contain a cluster of other CC chemokines.5,21 Recently,
Naruse et al22 have reported characterizing a yeast artificial chromosome contig of human chromosome 17q11.2. Contained within this contig was a gene identical to HCC-4 that they designated NCC-4 and described as CC chemokine-like; however, the open reading frame of this molecule was not reported and there no further
characterization of the putative chemokine was provided.22
Expression of HCC-4 mRNA and its regulation by IL-10.
The tissue distribution of HCC-4 was determined using commercially
available multiple tissue Northern blots. Surprisingly, we failed to
detect the 1,500-bp mRNA predicted from the size of the IMAGE clone we
had previously obtained. Instead, a 500-bp mRNA was detected in several
human immune tissues (Fig 2A). This smaller
message most likely results from use of the first polyA signal
sequence. Indeed, as discussed above, we have isolated cDNA clones from
several cDNA libraries that do appear to use this first
polyA+ signal. The results of the Northern blot analysis
were extended and confirmed by dot-blot analysis of a number of human
tissues (Fig 2B). Identical results were obtained using a smaller probe consisting of the coding region alone (data not shown). To determine what cell types might express HCC-4, we performed Southern blotting of
a number of human cDNA libraries constructed at DNAX. The results of
these experiments suggest weak expression by some lymphocytes, including natural killer (NK) cells,  T cells, and some T-cell clones (data not shown). However, the highest level of expression detected was in lipopolysaccharide (LPS) + IFN--activated human monocytes (Fig 3A). Interestingly, the
amount of HCC-4 cDNA detected in a similar library of monocytes
activated with IFN- and LPS in the presence of IL-10 was found to be
much higher than in a library of the same cells activated as before,
but without IL-10 and in the presence of a neutralizing anti-IL-10
MoAb (Fig 3A). In contrast, probing this same library with a cDNA
encoding the recently reported IL-10-inhibitable chemokine macrophage
inflammatory protein (MIP)-319 showed this
chemokine to be virtually absent from monocytes activated in the
presence of IL-10 (Fig 3A). The laddering effect in the HCC-4 cDNA blot
(and weakly in the MIP-3 blot; Fig 3A and B) results from the
variously sized inserts present in each library and has been observed
for other molecules, particularly when their mRNA exceeds 1.0 kb in
length23 (our unpublished observations).
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| Fig 2.
HCC-4 is expressed in multiple tissue types. RNA from
human immune tissues (A) or a multiple tissue dot-blot (B) were probed with a full-length HCC-4 probe. The 500-bp HCC-4 mRNA detected is
indicated with an arrow and appropriate size markers are shown. Dot
blot legend: A1, left atrium; B1, right atrium; C1, left ventricle; D1,
right ventricle; E1, interventricle septum; F1, pericardium; G1, human
DNA; H1, plasmid DNA; A2, frontal lobe; B2, temporal lobe; C2,
occipital lobe; D2, parietal lobe; E2, thalamus; F2, pons; G2,
cerebellum; H2, spinal cord; A3, parotid; B3, esophagus; C3, stomach;
D3, small intestine; E3, colon; F3, rectum; G3, liver; H3, gallbladder;
A4, throat; B4, bronchial trachea; C4, left lung; D4, right lung; E4,
diaphragm; F4, skeletal muscle; G4, tongue; H4, adipose tissue; A5,
kidney; B5, bladder; C5, prostate; D5, testis; E5, uterus; F5, breast;
G5, ovary; H5, placenta; A6, thyroid; B6, pancreas; C6, adrenal; D6,
tonsil; E6, thymus; F6, spleen; G6, lymph node; H6, appendix.
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| Fig 3.
Expression of HCC-4 mRNA is increased in the presence of
IL-10. (A) Two cDNA libraries were made from pools of elutriated human
monocytes stimulated for 1, 2, 6, 12, and 24 hours with LPS (5 µg/mL) and IFN- (200 U/mL) in the presence of IL-10 (200 U/mL)
or the neutralizing anti-IL-10 MoAb 19F1 (-IL-10; 10 µg/mL). The
cDNAs were treated with restriction enzymes to release their inserts
and analyzed by Southern blotting with either a 32P-labeled
cDNAs for HCC-4 or MIP-3, as indicated. For reference, the prominent
MIP-3 band is approximately 800 bp in length. (B) Total RNA was
obtained from elutriated human monocytes activated as described above
for 1 or 12 hours. Ten micrograms of total RNA (per lane) was analyzed
by Northern blotting with a 32P-labeled HCC-4 probe. The
sizes of the two HCC-4 messages found are indicated with arrows. The
equivalence of loading was assessed by ethidium bromide staining of the
RNA.
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To confirm the apparent upregulation of HCC-4 by IL-10, a Northern blot
of elutriated human monocytes activated with LPS for either 1 or 12 hours in the presence of either IL-10 or anti-IL-10 MoAb was
performed. This Northern blot analysis also showed two differently
sized HCC-4 mRNA transcripts. A smaller transcript of approximately 500 bp, consistent with the band observed in tissue Northern blots (Fig
2A), was detected in monocytes activated for 1 hour, but not in
monocytes activated for 12 hours, whereas a larger message of
approximately 1.5 kb, corresponding to the size of the original IMAGE
clone, was dramatically increased after 12 hours of activation, but
only in the presence of IL-10 (Fig 3B). The amount of 0.5-kb mRNA
expressed after 1 hour of activation was relatively unaffected or
slightly decreased in the presence of IL-10. The results of this
Northern blot confirm the results of the library Southern blot, because
HCC-4 mRNA was found to be more abundant in activated monocytes
cultured in the presence of IL-10. Furthermore, they suggest that the
increase seen in the cDNA libraries is largely attributable to an
increase in HCC-4 mRNA levels later in moncyte activation.
As previously mentioned, a potential mRNA instability sequence is
present between the first and second polyA+ signal
sequences of the 1.5-kb clone (Fig 1). This suggests the possibility
that expression of the 1.5-kb mRNA is regulated by this sequence and
that IL-10 provides a signal necessary for its stability. This would
also explain why the 0.5-kb message is relatively unaffected by IL-10,
because it would lack the putative destabilization sequence. This
finding is also consistent with the lack of a 1.5-kb message in the
Northern blot of human immune tissues (Fig 2A), which presumably
express negligible levels of IL-10. Future experiments will address the
regulation of HCC-4 in greater detail.
Biological activity of HCC-4.
To determine if HCC-4 possessed chemotactic activity we produced a
recombinant protein containing amino acids 24-120 of the full-length
molecule. Recombinant protein was purified by HPLC and the
amino-terminus was confirmed by sequencing. The recombinant HCC-4
demonstrated a dose-dependent ability to attract resting human
monocytes (Fig 4A) and THP-1 human monocyte
cells (Fig 4A, dashed line), with a peak response occurring at 1 µg/mL. Purified resting human T cells, B cells, and neutrophils were
also tested but demonstrated no apparent response (data not shown).
Controls for chemokinesis showed that the activity observed was indeed chemotaxis and not chemokinesis (data not shown).
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| Fig 4.
Monocytes respond to recombinant HCC-4. Recombinant HCC-4
was used at the indicated concentrations in (A) microchemotaxis assays
with human monocytes ( ) and THP-1 cells ( ) or (B)
Ca2+ flux assay with THP-1 monocyte cells. The results
shown are representative of three independent experiments. The
chemotatic index (number of cells migrated/background) was calculated
from the total cell count of five high power fields (1,000× at
eyepiece) from duplicate wells. For calcium flux, the reponse of THP-1
cells to a HCC-4 concentration of 10 7 mol/L is shown.
Desensitization by RANTES was at the same concentration. Flux buffer
alone was used as a negative control. The results are displayed as the
ratio of emmission 400:490 nm versus time.
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In addition to chemotaxis, recombinant HCC-4 induced a Ca2+
flux in THP-1 monocytes that was desensitized by prior incubation with
RANTES (Fig 4B). The Ca2+ flux in response to HCC-4 could
be observed at concentrations as low as 109 mol/L
(data not shown) and was dose-dependent with a maximal response
observed at 106 mol/L (Fig 4B). Experiments are
presently underway to more precisely identify the specific receptor(s)
used by HCC-4.
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DISCUSSION |
We have presented here the first characterization of this novel CC
chemokine. We have shown that is expressed in a number of human tissues
under normal circumstances, but whose expression by activated monocytes
is dramatically increased in the presence of IL-10. We have designated
this chemokine HCC-4 to denote is relationship to HCC-1. A previously
uncharacterized chemokine was already designated HCC-2 (now
Leukotactin-1),24 and the designation HCC-3 has also been
used for an apparent splice variant (uncharacterized) of HCC-1 (Gen
Bank accession no. Z70293).
HCC-4 is the first chemokine identified whose message is strongly
increased in the presence of IL-10. This suggests that expression of
HCC-4 mRNA would increase in the presence of IL-10. In contrast, other
chemokines whose regulation by IL-10 has been examined are either
downregulated by IL-10 or unaffected by its
presence.9,10,12-15 Interestingly, IL-10 seems to
accomplish the downregulation of chemokines through destabilization of
their mRNAs.10 However, IL-10 can also act to stabilize
mRNAs, as in the case of IL-1ra,3 and this may be the way
in which IL-10 regulates the expression of the 1.5-kb HCC-4 mRNA.
Future experiments will address the precise mechanism by which HCC-4 is
regulated.
An exception to the general IL-10 inhibition of chemokine expression is
monocyte chemotactic protein-1 (MCP-1), whose message in unstimulated
monocytes was found to be slightly increased in the presence of
IL-10.22 However, once the monocytes were activated by LPS,
MCP-1 mRNA was found to be downregulated in the presence of
IL-10.25 Thus, HCC-4 is uniquely upregulated by IL-10 and would most likely be present in a microenvironment that would be
inhibitory for other known chemokines. This, in turn, suggests a unique
biological role for HCC-4.
Phylogenetic analysis of HCC-4 shows it to be most closely related to
the chemokine HCC-1 (Fig 5). This is most
intriguing, because, like HCC-4, HCC-1 mRNA is expressed in a wide
range of tissues and the protein shows activity on
monocytes.16 Unlike most chemokines, HCC-1 was shown to be
expressed at high levels in normal serum (1 to 10 nmol/L); however,
little is known about the regulation of this gene.16
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| Fig 5.
Phylogenic analysis of HCC-4 and alignment with HCC-1.
(A) Phylogenic analysis of the relationship of HCC-4 to other human CC
chemokines is shown. HCC-3 (GenBank accession no. Z70293) is a
potential splice variant of HCC-1. MIP-3 (GenBank accession no. P55773)
is a potential splice variant of MPIF-1. (B) CLUSTAL alignment of HCC-4
and HCC-1. Similar amino acid residues are boxed, whereas identities
are boxed and shaded.
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The region of highest homology between HCC-1 and HCC-4 extends from
Cys-3 beyond Cys-4 and terminates just before a series of three
prolines separated by two intervening amino acid residues. Just beyond
these prolines a potential N-linked glycosylation site (NLS) is found
in the HCC-4 sequence. It is not known whether this site is used in
vivo, but antibodies are being raised to HCC-4 to facilitate such an
analysis as well as to isolate the native form of the protein. It is
possible that C-terminal modifications might modulate the biological
activity of HCC-4, although we have observed that supernatant from
HCC-4-transfected COS cells also exhibits chemotactic activity for
monocytes, but not for lymphocytes.
In addition to its chemotatic effects on human monocytes and THP-1
monocyte cells, we also demonstrated that HCC-4 can cause a
Ca2+ flux in THP-1 cells. This flux was maximal at 1 µmol/L and was completely inhibited by prior exposure of THP-1 to
RANTES, suggesting that HCC-4 shares a receptor with RANTES. However,
HCC-4 was unable to desensitize the RANTES response (data not shown);
thus, HCC-4 may bind only a subset of RANTES receptors present on the
surface of THP-1.
Historically, chemokines have been associated with the initiation and
augmentation of inflammatory responses. They have been shown to attract
inflammatory leukocytes, to activate neutrophils and granulocytes, and
to be upregulated by cytokines of an inflammatory nature while being
downregulated by anti-inflammatory cytokines. Other
molecules whose expression is regulated by IL-10 in this fashion are
associated with the resolution of an inflammatory response (reviewed in
de Vries and de Waal Malefyt2). We suggest, by analogy,
that HCC-4 may not be involved in the initiation of an inflammatory
response, but rather in its resolution. Although this idea would at
first appear to be in conflict with the ability of HCC-4 to attract
monocytes, this is not necessarily the case.
Several observations suggest that the primary biological activity of
HCC-4 and related chemokines may not be chemotaxis, but might instead
be some other function. First, the in vitro chemotactic effects of
HCC-4 on monocytes require relatively high concentrations when compared
with other chemokines. Similarly, HCC-1, the chemokine most closely
related to HCC-4, has no demonstrated chemotactic effects on
monocytes,16 although, like HCC-4, it can generate a
Ca2+ flux in these cells. Second, the mRNA for both HCC-1
and HCC-4 is expressed constitutively in a wide range of
tissues16 (Fig 2B), and the HCC-1 protein is present at
high levels in normal serum.16 Finally, as already
discussed, increased expression of HCC-4 in the presence of IL-10 is
not consistent with continued infiltration of inflammatory cells.
One possible alternative is that HCC-4 competes for binding to
chemokine receptors used by inflammatory chemokines, thus regulating their activity. Their presence in the circulation (or in tissue) at
high levels would then inhibit the directed migration of cells in
response to chemokines such as MIP-1 and RANTES, thus slowing or
blocking continued infiltration of inflammatory leukocytes. In any
case, HCC-4 and related chemokines have a number of unusual characteristics that suggest that they do not function like typical chemokines (if such a thing exists) and that may lead us to discover novel functions for these intriguing molecules.
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NOTE ADDED IN PROOF |
While this manuscript was in press an article appeared describing HCC-4
as liver-expressed chemokine (LEC). The authors report two LEC mRNAs
which are identical to the HCC-4 mRNAs.26
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FOOTNOTES |
Submitted November 17, 1997;
accepted January 15, 1998.
DNAX Research Institute is supported by Schering-Plough Corp.
Address reprint requests to Albert Zlotnik, PhD, DNAX Research
Institute, 901 California St, Palo Alto, CA 94304; e-mail: zlotnik{at}dnax.org.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
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ACKNOWLEDGMENT |
The authors acknowledge Anne-Marie O'Farrell and René de Waal
Malefyt for providing mRNA blots for Northern analysis and Junichi
Naganuma for assistance with expression analysis. We also acknowledge
the contribution of R&D Systems in the production of recombinant HCC-4.
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Abstract
Introduction
Abstract