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IMMUNOBIOLOGY
From the Department of Cell Biology and Histology and
the Department of Dermatology, Academic Medical Center, University of
Amsterdam, The Netherlands.
Interleukin-12 p70 (IL-12p70) heterodimer, composed of p35 and p40
subunits, is a major Th1-driving cytokine, promoting cell-mediated immunity. In contrast, IL-12p40 homodimer, secreted by APC in the
absence of p35 expression, and free p40 monomer do not mediate IL-12
activity but act as IL-12 antagonists. Here it is reported that
prostaglandin E2 (PGE2), an inflammatory
mediator with a previously known Th2-driving function, dose-dependently
enhances the IL-12p40 mRNA expression and the secretion of IL-12p40
protein in human tumor necrosis factor-alpha (TNF Bioactive interleukin-12 p70 (IL-12p70) is a
heterodimer composed of 2 subunits: p35 and p40.1 Although
p35 is expressed in numerous cell types, p40 expression is more
restricted and determines the ability of a given cell-type to produce
bioactive IL-12.1 However, in the cells that are capable
of producing both IL-12 subunits, it is the p35 subunit, produced in
much lower amounts than p40, that plays the role of a limiting factor
and determines the amount of bioactive IL-12p70 that is
secreted.1,2 IL-12p70 heterodimer is a major Th1-driving
cytokine. In contrast, p40 homodimer, secreted by antigen presenting
cells (APCs) in the absence of p35 production, and to a lesser extent
the p40 monomer, were shown to act as antagonists of mouse and human
IL-12 receptors1,3-5 and to inhibit IL-12-dependent
immune functions in vitro and in vivo.6-13
Bioactive IL-12p70 is produced by dendritic cells (DCs) during their
interaction with Th cells, as a result of CD40-CD40L interaction
between these 2 cell types.14-18 Although CD40-triggering alone provides a sufficient signal for the induction of IL-12p40 and
several other cytokines, effective induction of IL-12p70 depends on the
presence of an additional signal that can be provided by at least 2 of
the Th cell-produced cytokines, interferon gamma (IFN Prostaglandin E2 (PGE2), is a common
inflammatory mediator with a Th2-driving role at several levels of
immune response. PGE2 selectively impairs the production of
IFN In apparent contrast, PGE2 was recently reported to
synergize with tumor necrosis factor-alpha (TNF Having in mind the opposite roles played by IL-12p70 and
IL-12p40 and the different requirements for the induction of either factor in human DCs,1,2,17-19 we tested whether the
enhancement of IL-12p40 production in TNF Generation of "tissue-type" immature
CD1a+CD83 Analysis of cytokine production
Cytokine measurements IL-12p70 ELISA (sensitivity, 3 pg/mL),27 was performed with use of p70-specific mAb 20C2 (a gift from Dr M.K. Gately, Hoffmann-La Roche, Nutley, NJ) and p40-specific C8.6 mAb (a gift from Dr G. Trinchieri, The Wistar Institute, Philadelphia, PA). IL-12p40-specific ELISAs, recognizing p40 monomer, p40 homodimer, and p70 (p40 + p35) heterodimer were performed as described elsewhere. 2,25Analysis of p35 and p40 mRNA expression DCs (3 × 105 cells in 2 mL) were stimulated with the combination of TNF (50 ng/mL) and PGE2
(10 6 M) in the presence of IFN (1000 U/mL) or with LPS
(250 ng/mL) and IFN (1000 U/mL), as indicated. Unstimulated DCs and
DCs exposed to IFN alone were used as negative controls. Cells were
lyzed after 6 hours and total RNA was isolated using the RNeasy Kit (Qiagen, Hilden, Germany). First-strand cDNA was synthesized from the
total amount of RNA using Moloney murine leukemia virus (mMLV)-derived reverse transcriptase (RT) (MBI fermentas, Vilnius, Lithuania). Polymerase chain reaction (PCR) amplification of p35 (3:l of cDNA; 40 cycles) and p40 (2:l of cDNA; 35 cycles) was carried out using the p35
and p40 primers,2 resulting in the products of 533 base
pair (bp) and 267 bp, respectively. PCR specific for human b2m (1:l
cDNA, 35 cycles) was performed with specific primers,32 resulting in the product of 286 bp. Ethidium bromide-stained PCR products were analyzed on agarose gel by Eagle-Eye (Stratagene, La
Jolla, CA) and SigmaGel software (SPSS Science, Jandel
Scientific Software, Chicago, IL).
The induction of IL-12p40 mRNA and
protein in DCs by TNF -induced final maturation of DCs,26,30,31 which was
accompanied by the production of at least a p40 subunit of
IL-12.30 To test whether the production of p40 in these
conditions is accompanied by the induction of an IL-12p35 subunit and
the secretion of bioactive IL-12p70, we analyzed the regulation of both
IL-12 forms in TNF -activated DCs by PGE2.
In accordance with the previous report, immature DCs exposed to TNF
Previously, we have shown that the physiologic levels of CD40
triggering, by CD40L-expressing Th cells, for example, are sufficient to induce IL-12p40 production, but the efficient induction of IL-12p70
requires an additional IFN Since the secretion of bioactive IL-12p70 requires the production of
both IL-12 subunits, p35 and p40, we analyzed the induction of mRNA
encoding either of these subunits. As shown in Figure 2, both p35 and p40 expression were
observed in DCs stimulated with LPS and IFN
PGE2 inhibits the production of both forms of IL-12 in DCs stimulated with the "classical IL-12 inducers" CD40L or LPS To test whether PGE2 differentially regulates the production of IL-12p40 and IL-12p70, also during the stimulation of DCs with other stimuli, we added increasing concentrations of PGE2 to DC cultures stimulated with 2 classical IL-12 inducers known to induce both IL-12p40 and bioactive IL-12p70 LPS and
CD40L-transfected J558 cells (J558-CD40L) that express very high levels
of CD40L. As shown in Figure 3,
PGE2 inhibited the production of both IL-12p70 and IL-12p40
production induced by either of these stimuli.
The current demonstration that the PGE2-assisted
enhancement of IL-12p40 production in TNF PGE2 is known to exert Th2-promoting and
IL-12-antagonistic activity via several distinct mechanisms, affecting
both APCs and Th cells. It suppresses the production of bioactive
IL-12p70, both directly24-26 and by inhibiting the Th-cell
production of IFN Human DCs matured in the presence of PGE2 showed reduced
IL-12-producing capacity, compared with mature DCs obtained in the presence of high doses of IL-1 The presently described selective induction of IL-12p40 suggests the existence of an additional level of Th2-promoting and IL-12-antagonistic activity of PGE2, mediated by p40 homodimer, or by free IL-12p40. Both in mouse and in human systems, it was demonstrated that p40 homodimer and to a lesser extent also the product of its dissociation, free p40 monomer, can suppress the responsiveness to IL-12 by competitively inhibiting the IL-12 receptor binding.1,3-5 This activity is very well pronounced in mice where p40 homodimer exerts the antagonistic activity with an IC50 of 1-10 ng/mL, whereas in humans concentrations at least 10-fold higher are required.3-5 Mouse p40 homodimer was shown to effectively antagonize IL-12 activity in vivo, as a factor rescuing the animals from lethal LPS-induced shock and suppressing the Th1-dominated inflammatory responses in several models of chronic inflamation, transplantation, and cancer.6-12 In humans, high levels of IL-12p40 in peritoneal fluid were postulated to play an IL-12-antagonistic role in endometriosis, as a factor locally inhibiting the activity of natural killer (NK) cells.13 Unfortunately, poor stability of human p40 homodimer1 constitutes a serious obstacle in analyzing its physiologic role, and its potential therapeutic in vivo use in transplantation and autoimmune diseases. For the same reason, we could not determine if the PGE2-induced IL-12p40 was released from DCs as p40 homodimer or as p40 monomer, a less potent IL-12 antagonist.1 Current demonstration of the selective induction of
inactive/antagonistic IL-12p40 argues against the proposed
Th1-promoting role for PGE2 at the inflammatory
sites.30 On the contrary, selective induction of IL-12p40
by PGE2 is likely to contribute to selective suppression of
Th1-type responses in chronic inflammation, and may play a role in the
immune deviation induced by the PGE2-producing tumors.35-40 Although PGE2 enhances the
expression of costimulatory molecules on DCs and increases their
ability to stimulate CD4+ and CD8+ T
cells,26,30,31 the ability of PGE2 to induce
IL-12p40 production and to suppress the IL-12p70-producing ability of
DCs25,26 may impair the tumoricidal functions of Th1, NK
cells, and cytotoxic T lymphocytes. Multiple levels of IL-12
antagonism of PGE2 may have a negative impact on the
effectiveness of immunotherapeutic protocols that use PGE2
in combination with IL-1
Submitted October 20, 2000; accepted January 5, 2001.
Supported by Fundação para a Ciência e a Tecnologia, Lisbon, Portugal (grant no. PRAXIS XXI/BD/9195/96 to P.L.V.).
Correspondence: Pawe
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.
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D. W. O'Neill, S. Adams, and N. Bhardwaj Manipulating dendritic cell biology for the active immunotherapy of cancer Blood, October 15, 2004; 104(8): 2235 - 2246. [Abstract] [Full Text] [PDF] |
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F. Marteau, D. Communi, J.-M. Boeynaems, and N. Suarez Gonzalez Involvement of multiple P2Y receptors and signaling pathways in the action of adenine nucleotides diphosphates on human monocyte-derived dendritic cells J. Leukoc. Biol., October 1, 2004; 76(4): 796 - 803. [Abstract] [Full Text] [PDF] |
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X. Chen, K. Doffek, S. L. Sugg, and J. Shilyansky Phosphatidylserine Regulates the Maturation of Human Dendritic Cells J. Immunol., September 1, 2004; 173(5): 2985 - 2994. [Abstract] [Full Text] [PDF] |
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A. Rivas-Carvalho, M. A. Meraz-Rios, L. Santos-Argumedo, S. Bajana, G. Soldevila, M. E. Moreno-Garcia, and C. Sanchez-Torres CD16+ human monocyte-derived dendritic cells matured with different and unrelated stimuli promote similar allogeneic Th2 responses: regulation by pro- and anti-inflammatory cytokines Int. Immunol., September 1, 2004; 16(9): 1251 - 1263. [Abstract] [Full Text] [PDF] |
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M. Galgani, V. De Rosa, S. De Simone, A. Leonardi, U. D'Oro, G. Napolitani, A. M. Masci, S. Zappacosta, and L. Racioppi Cyclic AMP Modulates the Functional Plasticity of Immature Dendritic Cells by Inhibiting Src-like Kinases through Protein Kinase A-mediated Signaling J. Biol. Chem., July 30, 2004; 279(31): 32507 - 32514. [Abstract] [Full Text] [PDF] |
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R. M. Johnson Murine Oviduct Epithelial Cell Cytokine Responses to Chlamydia muridarum Infection Include Interleukin-12-p70 Secretion Infect. Immun., July 1, 2004; 72(7): 3951 - 3960. [Abstract] [Full Text] [PDF] |
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S. Kubo, H. K. Takahashi, M. Takei, H. Iwagaki, T. Yoshino, N. Tanaka, S. Mori, and M. Nishibori E-Prostanoid (EP)2/EP4 Receptor-Dependent Maturation of Human Monocyte-Derived Dendritic Cells and Induction of Helper T2 Polarization J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 1213 - 1220. [Abstract] [Full Text] [PDF] |
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A. Mazzoni and D. M. Segal Controlling the Toll road to dendritic cell polarization J. Leukoc. Biol., May 1, 2004; 75(5): 721 - 730. [Abstract] [Full Text] [PDF] |
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R. Rouas, P. Lewalle, F. El Ouriaghli, B. Nowak, H. Duvillier, and P. Martiat Poly(I:C) used for human dendritic cell maturation preserves their ability to secondarily secrete bioactive IL-12 Int. Immunol., May 1, 2004; 16(5): 767 - 773. [Abstract] [Full Text] [PDF] |
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P. Athanassopoulos, L. M.B. Vaessen, A. P.W.M. Maat, A. H.M.M. Balk, W. Weimar, and A. J.J.C. Bogers Peripheral blood dendritic cells in human end-stage heart failure and the early post-transplant period: evidence for systemic Th1 immune responses Eur. J. Cardiothorac. Surg., April 1, 2004; 25(4): 619 - 626. [Abstract] [Full Text] [PDF] |
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C. C. Bowman and K. L. Bost Cyclooxygenase-2-Mediated Prostaglandin E2 Production in Mesenteric Lymph Nodes and in Cultured Macrophages and Dendritic Cells after Infection with Salmonella J. Immunol., February 15, 2004; 172(4): 2469 - 2475. [Abstract] [Full Text] [PDF] |
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M. A. P. Oliveira, G. M. A. C. Lima, M. T. Shio, P. J. M. Leenen, and I. A. Abrahamsohn Immature macrophages derived from mouse bone marrow produce large amounts of IL-12p40 after LPS stimulation J. Leukoc. Biol., November 1, 2003; 74(5): 857 - 867. [Abstract] [Full Text] [PDF] |
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A. Soruri, J. Riggert, T. Schlott, Z. Kiafard, C. Dettmer, and J. Zwirner Anaphylatoxin C5a Induces Monocyte Recruitment and Differentiation into Dendritic Cells by TNF-{alpha} and Prostaglandin E2-Dependent Mechanisms J. Immunol., September 1, 2003; 171(5): 2631 - 2636. [Abstract] [Full Text] [PDF] |
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M. Jefford, M. Schnurr, T. Toy, K.-A. Masterman, A. Shin, T. Beecroft, T. Y. Tai, K. Shortman, M. Shackleton, I. D. Davis, et al. Functional comparison of DCs generated in vivo with Flt3 ligand or in vitro from blood monocytes: differential regulation of function by specific classes of physiologic stimuli Blood, September 1, 2003; 102(5): 1753 - 1763. [Abstract] [Full Text] [PDF] |
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M. Martin, S. M. Michalek, and J. Katz Role of Innate Immune Factors in the Adjuvant Activity of Monophosphoryl Lipid A Infect. Immun., May 1, 2003; 71(5): 2498 - 2507. [Abstract] [Full Text] [PDF] |
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M. Dauer, B. Obermaier, J. Herten, C. Haerle, K. Pohl, S. Rothenfusser, M. Schnurr, S. Endres, and A. Eigler Mature Dendritic Cells Derived from Human Monocytes Within 48 Hours: A Novel Strategy for Dendritic Cell Differentiation from Blood Precursors J. Immunol., April 15, 2003; 170(8): 4069 - 4076. [Abstract] [Full Text] [PDF] |
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S. Sharma, M. Stolina, S.-C. Yang, F. Baratelli, J. F. Lin, K. Atianzar, J. Luo, L. Zhu, Y. Lin, M. Huang, et al. Tumor Cyclooxygenase 2-dependent Suppression of Dendritic Cell Function Clin. Cancer Res., March 1, 2003; 9(3): 961 - 968. [Abstract] [Full Text] [PDF] |
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S. Al-Darmaki, H. A. Schenkein, J. G. Tew, and S. E. Barbour Differential Expression of Platelet-Activating Factor Acetylhydrolase in Macrophages and Monocyte-Derived Dendritic Cells J. Immunol., January 1, 2003; 170(1): 167 - 173. [Abstract] [Full Text] [PDF] |
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M. Fogel, J. A. Long, P. J. Thompson, and J. W. Upham Dendritic cell maturation and IL-12 synthesis induced by the synthetic immune-response modifier S-28463 J. Leukoc. Biol., November 1, 2002; 72(5): 932 - 938. [Abstract] [Full Text] [PDF] |
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J. Li, U. M. Padigel, P. Scott, and J. P. Farrell Combined Treatment with Interleukin-12 and Indomethacin Promotes Increased Resistance in BALB/c Mice with Established Leishmania major Infections Infect. Immun., October 1, 2002; 70(10): 5715 - 5720. [Abstract] [Full Text] [PDF] |
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Y. Moon and J. J. Pestka Vomitoxin-Induced Cyclooxygenase-2 Gene Expression in Macrophages Mediated by Activation of ERK and p38 but Not JNK Mitogen-Activated Protein Kinases Toxicol. Sci., October 1, 2002; 69(2): 373 - 382. [Abstract] [Full Text] [PDF] |
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F. Huaux, M. Arras, D. Tomasi, V. Barbarin, M. Delos, J.-P. Coutelier, A. Vink, S. H. Phan, J.-C. Renauld, and D. Lison A Profibrotic Function of IL-12p40 in Experimental Pulmonary Fibrosis J. Immunol., September 1, 2002; 169(5): 2653 - 2661. [Abstract] [Full Text] [PDF] |
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E. Scandella, Y. Men, S. Gillessen, R. Forster, and M. Groettrup Prostaglandin E2 is a key factor for CCR7 surface expression and migration of monocyte-derived dendritic cells Blood, July 30, 2002; 100(4): 1354 - 1361. [Abstract] [Full Text] [PDF] |
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T. Luft, M. Jefford, P. Luetjens, T. Toy, H. Hochrein, K.-A. Masterman, C. Maliszewski, K. Shortman, J. Cebon, and E. Maraskovsky Functionally distinct dendritic cell (DC) populations induced by physiologic stimuli: prostaglandin E2 regulates the migratory capacity of specific DC subsets Blood, July 30, 2002; 100(4): 1362 - 1372. [Abstract] [Full Text] [PDF] |
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A. J. Masterson, C. C. Sombroek, T. D. de Gruijl, Y. M. F. Graus, H. J. J. van der Vliet, S. M. Lougheed, A. J. M. van den Eertwegh, H. M. Pinedo, and R. J. Scheper MUTZ-3, a human cell line model for the cytokine-induced differentiation of dendritic cells from CD34+ precursors Blood, June 28, 2002; 100(2): 701 - 703. [Abstract] [Full Text] [PDF] |
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B R Lauwerys, J Van Snick, and F A Houssiau Serum IL-12 in systemic lupus erythematosus: absence of p70 heterodimers but presence of p40 monomers correlating with disease activity Lupus, June 1, 2002; 11(6): 384 - 387. [Abstract] [PDF] |
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H. Harizi, M. Juzan, V. Pitard, J.-F. Moreau, and N. Gualde Cyclooxygenase-2-Issued Prostaglandin E2 Enhances the Production of Endogenous IL-10, Which Down-Regulates Dendritic Cell Functions J. Immunol., March 1, 2002; 168(5): 2255 - 2263. [Abstract] [Full Text] [PDF] |
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T. Kambayashi, R. P. A. Wallin, and H.-G. Ljunggren cAMP-elevating agents suppress dendritic cell function J. Leukoc. Biol., December 1, 2001; 70(6): 903 - 910. [Abstract] [Full Text] [PDF] |
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