Conventional protein kinase C and atypical protein kinase Czeta differentially regulate macrophage production of tumour necrosis factor-alpha and interleukin-10.
In chronic inflammatory diseases such as rheumatoid arthritis, joint macrophages/monocytes are the major source of pro- and anti-inflammatory cytokines. Little is understood regarding the signalling pathways which determine the production of the pro-inflammatory cytokine, tumour necrosis factor-alpha (TNF-alpha) and the anti-inflammatory cytokine, interleukin-10 (IL-10). Two pathways integral to macrophage function are the protein kinase C (PKC)- and the cAMP-dependent pathways. In this report, we have investigated the involvement of PKC and cAMP in the production of TNF-alpha and IL-10 by peripheral blood monocyte-derived macrophages. The utilization of the PKC inhibitors Go6983, Go6976 and RO-32-0432 demonstrated a role for conventional PKCs (alpha and beta) in the production of TNF-alpha in response to stimulation by lipopolysaccharide and phorbol 12-myristate 13-acetate (PMA)/ionomycin. PKC stimulation resulted in the downstream activation of the p42/44 mitogen-activated protein kinase (MAPK) pathway which differentially regulates TNF-alpha and IL-10. The addition of cAMP however, suppressed activation of this MAPK and TNF-alpha production. Cyclic-AMP augmented IL-10 production and cAMP response element binding protein activation upon stimulation by PMA/ionomycin. In addition, cAMP activated PKCzeta; inhibition of which, by a dominant negative adenovirus construct, selectively suppressed IL-10 production. These observations suggest that pro-inflammatory and anti-inflammatory cytokines are differentially regulated by PKC isoforms; TNF-alpha being dependent on conventional PKCs (alpha and beta) whereas IL-10 is regulated by the cAMP-regulated atypical PKCzeta.
Foey
Andrew D
AD
Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, London, UK. afoey@eeclarke_freeserve.co.uk
Brennan
Fionula M
FM
D002478:Cells, Cultured; D000242:Cyclic AMP / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis*; D015759:Ionomycin / Q000276:immunology; D007527:Isoenzymes / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D000099221:Protein Kinase C zeta
D000242:Cyclic AMP; D016753:Interleukin-10; D015759:Ionomycin; D007527:Isoenzymes; D019950:Mitogen-Activated Protein Kinase 1; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D014409:Tumor Necrosis Factor-alpha; D000099221:Protein Kinase C zeta