ABSTRACT
cAMP mediated signaling may play a suppressive role in immune response. We previously found that the cAMP-elevators (CTx and 8-Br-cAMP) inhibited IL-12, IL-1a, IL-6 gene expression, but increased the transcriptional levels of IL-10 and IL-1Ra in LPS-treated murine peritoneal macrophages. The present study examined a possible molecular mechanism involved in cAMP elevators-induced inhibition of IL-12 p40 expression in response to LPS. Our data demonstrated that cAMP elevators downregulated IL-12 p40 mRNA expression and IL-12 p70 production in murine peritoneal macrophages. Subsequent studies revealed that cAMP-elevators blocked phosphorylation of p38 MAPK, but did not affect the activity of NF-κB binding to IL-12 promoter (−136/−112). This is the first report that cAMP elevators inhibit LPS-induced IL-12 production by a mechanism that is associated, at least in part, with p38-dependent inhibition by cAMP signaling pathways.
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Abbreviations
- IL-12:
-
interleukin 12
- NF-κB:
-
nuclear factor κB
- TNF-α:
-
trmor necrosis factor-α
References
Feng W, Wang Y, Zhang J, Wang X, Li C, Chang Z . Effects of CTx and 8-bromo-cAMP on LPS-induced gene expression of cytokines in murine peritoneal macrophages. Biochemical and Biophysical Research Communications 2000; 269:570–3.
Caivano M, Cohen P . Role of mitogen-activated protein kinase cascades in mediating lipopolysaccharide-stimulated induction of cyclooxygenase-2 and IL-1 beta in RAW264 macrophages. J Immunol 2000; 164:3018–25.
Remick DG, Newcomb DE, Bolgos GL, Call DR . Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide vs. cecal ligation and puncture. Shock 2000; 13:110–6.
Cambronero R, Sewell WA, North ME, Webster AD, Farrant J . Up-regulation of IL-12 in monocytes: a fundamental defect in common variable immunodeficiency. J Immunol 2000; 164:488–94.
Nick JA, Young SK, Brown KK, et al. Role of p38 mitogen-activated protein kinase in a murine model of pulmonary inflammation. J Immunol 2000; 164:2151–9.
Kobayashi H, Kobayashi M, Heming TA, Bidani A, Pollard RB, Suzuki F . Cytokine production by rabbit alveolar macrophages: differences between activated and suppressor cell phenotypes. Immunol Lett 1999; 69:339–46.
Brightbill HD, Plevy SE, Modlin RL, Smale ST . A prominent role for Sp1 during lipopolysaccharide-mediated induction of the IL-10 promoter in macrophages. J Immunol 2000; 164:1940–51.
Pue CA, Mortensen RF, Marsh CB, Pope HA, Wewers MD . Acute phase levels of C-reactive protein enhance IL-1 beta and IL-1ra production by human blood monocytes but inhibit IL-1 beta and IL-1ra production by alveolar macrophages. J Immunol 1996; 156:1594–600.
Kammer GM . The adenylate cyclase-cAMP-protein kinase A pathway and regulation of the immune response. Immunol Today 1988; 9:222–9.
Uotila P . The role of cyclic AMP and oxygen intermediates in the inhibition of cellular immunity in cancer. Cancer Immunol Immunother. 1996; 43:1–9.
Zhong WW, Burke PA, Drotar ME, Chavali SR, Forse RA . Effects of prostaglandin E2, cholera toxin and 8-bromo-cyclic AMP on lipopolysaccharide-induced gene expression of cytokines in human macrophages. Immunology 1995; 84:446–52.
Goetzl EJ, Pankhaniya RR, Gaufo GO, Mu Y, Xia M, Sreedharan SP . Selectivity of effects of vasoactive intestinal peptide on macrophages and lymphocytes in compartmental immune responses. Ann N Y Acad Sci 1998; 840:540–50.
Delgado M, Martinez C, Pozo D, et al. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activation polypeptide (PACAP) protect mice from lethal endotoxemia through the inhibition of TNF-a and IL-6. J Immunol 1999; 162:1200–5.
Abbas AK, Lichtman AH, and Pober JS . Eds. Cellular and Molecular Immunology. Saunders Press: Philadelphia 1997:249–77.
Delgado M, Ganea D . Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit interleukin-12 transcription by regulating nuclear factor κB and Ets activation. J Biol Chem 1999; 274:31930–40.
Zhang JS, Feng WG, Li CL, Wang XY, Chang ZL . NF-κB regulates the LPS-induced expression of interleukin 12 p40 in murine peritoneal macrophages: roles of PKC, PKA, ERK, p38 MAPK, and proteasome. Cell Immunol 2000; 204:38–45.
Lu HT, Yang DD, Wysk M, Gatti E, Mellman I, Davis RJ, Flavell RA . Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. EMBO J 1999; 18:1845–57.
Aicher A, Shu GL, Magaletti D, Mulvania T, Pezzutto A, Craxton A, Clark EA . Differential role for p38 mitogen-activated protein kinase in regulating CD40-induced gene expression in dendritic cells and B cells. J Immunol 1999; 163:5786–95.
Szabo G, Girouard L, Mandrekar P, Catalano D . Regulation of monocyte IL-12 production: augmentation by lymphocyte contact and acute ethanol treatment, inhibition by elevated intracellular camp. Int J Immunopharmacol 1998; 20:491–503.
Link AA, Kino T, Worth JA, McGuire JL, et al. Ligand-activation of the adenosine A2a receptors inhibits IL-12 production by human monocytes. J Immunol 2000; 164:436–42.
Andrews NC, Faller DV . A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucleic Acids Res 1991; 19:2499.
Zhu T, Lobie PE . Janus kinase 2-dependent activation of p38 mitogen-activated protein kinase by growth hormone. Resultant transcriptional activation of ATF-2 and CHOP, cytoskeletal re-organization and mitogenesis. J Biol Chem 2000; 275:2103–14.
Brinkman BM, Telliez JB, Schievella AR, Lin LL, Goldfeld AE . Engagement of tumor necrosis factor (TNF) receptor 1 leads to ATF-2- and p38 mitogen-activated protein kinase-dependent TNF-alpha gene expression. J Biol Chem 1999; 274:30882–6.
Hanafusa H, Ninomiya-Tsuji J, Masuyama N, et al. Involvement of the p38 mitogen-activated protein kinase pathway in transforming growth factor-beta-induced gene expression. J Biol Chem 1999; 274:27161–7.
Guha M, Mackman N . LPS induction of gene expression in human monocytes. Cell Signal 2001; 13:85–94.
Lin MQ, Chang ZL . Immunomodulated Signaling in Macrophages: Regulation of the MAPK Signaling Pathways by PKA and PKC. Acta Biochimica et Biophysica Sinica 1999; 31:701–6.
Feng WG, Chang ZL . Expression of cytokine mRNA during immuno-modulation of murine suppressor macrophages. Cell Res 1998; 8:317–22.
Hu YJ, Zang L, Wu YD, Sun B . High IFN-a expression is associated with the induction of experimental autoimmune uveitis (EAU) in Fischer 344 rat. Cell Res 2001; 11:293–300.
Geng JG . Directional migration of leukocytes: their pathological roles in inflammation and strategies for development of anti-inflammatory therapies. Cell Res 2001; 11:85–8.
Acknowledgements
This work was supported by Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and the grant from Ministry of Science and Technology (G1999054201) and National Natural Science Foundation of China (39870717). We would like to thank Prof. Kozel TR of Department of Microbiology of University Nevada, Reno, USA for his helpful reviewing of the manuscript.
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FENG, W., WANG, Y., ZHANG, J. et al. cAMP elevators inhibit LPS-induced IL-12 p40 expression by interfering with phosphorylation of p38 MAPK in Murine Peritoneal Macrophages. Cell Res 12, 331–337 (2002). https://doi.org/10.1038/sj.cr.7290135
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DOI: https://doi.org/10.1038/sj.cr.7290135
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