Conventional protein kinase C and atypical protein kinase Cζ differentially regulate macrophage production of tumour necrosis factor‐α and interleukin‐10

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Abstract
Summary: 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‐α (TNF‐α) 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‐α 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 (α and β) in the production of TNF‐α 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‐α and IL‐10. The addition of cAMP however, suppressed activation of this MAPK and TNF‐α production. Cyclic‐AMP augmented IL‐10 production and cAMP response element binding protein activation upon stimulation by PMA/ionomycin. In addition, cAMP activated PKCζ; 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‐α being dependent on conventional PKCs (α and β) whereas IL‐10 is regulated by the cAMP‐regulated atypical PKCζ.

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