CD40 Signaling of Monocyte Inflammatory Cytokine Synthesis through an ERK1/2-dependent Pathway

Abstract

Ligation of CD40 on monocytes through its interaction with CD40 ligand (CD154) present on activated T helper cells, results in activation of monocyte inflammatory cytokine synthesis and rescue of monocytes from apoptosis induced through serum deprivation. Both of these consequences of CD40 stimulation have been shown to be dependent on the induction of protein tyrosine kinase activity. CD40-mediated activation of protein tyrosine kinase activity and subsequent inflammatory cytokine production are abrogated by treatment of monocytes with the T helper type 2 cytokines interleukin 4 (IL-4) and interleukin 10 (IL-10). In the current study we demonstrate that stimulation of monocytes through CD40 resulted in the phosphorylation and activation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) mitogen-activated protein kinases, whereas phosphorylation of mitogen-activated protein kinases family members p38 and c-Jun N-terminal kinase was not observed in response to this stimuli over the time course examined. PD98059, an inhibitor of the upstream activator of ERK1/2, the MAP/ERK kinase MEK1/2, suppressed IL-1␤ and tumor necrosis factor-␣ production in a dose-dependent fashion. Pretreatment of monocytes with IL-4 and IL-10 inhibited CD40-mediated activation of ERK1/2 kinase activity when used individually, and are enhanced in effectiveness when used in combination. Together, the data demonstrate that CD40-mediated induction of IL-1␤ and tumor necrosis factor-␣ synthesis is dependent on a MEK/ERK pathway which is obstructed by signals generated through the action of IL-4 and IL-10.

The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes

“…Whether or not stimulation of CD40 is involved in adipocyte differentiation or apoptosis deserves to be studied. Earlier studies showed that CD40 signalling results in the activation of the MAPK/ NF-κB pathways in monocytes/macrophages [33][34][35], thereby stimulating CD40-mediated induction of inflammatory cytokine synthesis. We found that in human adipocytes rCD40L treatment activated MAPKs and induced IκB protein degradation, which is known to activate and promote nuclear translocation of NF-κB, suggesting that increases in sCD40L or T-lymphocyte-expressing CD40L may play a role in the elevated activities of these factors in obesity.…”

Amplification of the synovial inflammatory response through activation of mitogen‐activated protein kinases and nuclear factor κB using ligation of CD40 on CD14+ synovial cells from patients with rheumatoid arthritis

“…Moreover, involvement of Ras and Raf, the upstream regulators of ERK, in the regulation of TNF␣ production has been reported (26). Several investigators demonstrated that PD98059, an inhibitor of MEK, suppressed TNF␣ production in LPS-stimulated or CD154-stimulated monocytes (36)(37)(38)(39). Conversely, it has been reported that p38 is involved not only in the translation, but also in the stabilization of TNF␣ mRNA (40)(41)(42).…”

Interleukin-10 attenuates vascular responses to endothelin-1 via effects on ERK1/2-dependent pathway

“…IL-10 also suppresses cyclooxgenase-2 expression by downregulation of p38 MAPK and ERK2 (31). Moreover, several reports have shown that IL-10 inhibits ERK1/2 activity and that this is important, for example, for the downregulation of polymorphonuclear neutrophil functions and CD40-mediated induction of IL-1␤ and TNF-␣ synthesis by monocytes (6,33,39).…”

“…In polymorphonuclear neutrophils, IL-10 exerts its anti-inflammatory properties by downregulating functions such as NADPH oxidase activation and reactive oxygen species production (6). Many of the anti-inflammatory actions of IL-10 are associated with inhibition of ERK1/2 activity or the MEK/ERK pathway (5,38,39).…”

“…IL-10 inhibits chemokine production, antigen presentation, and antigen-specific T cell proliferation and is a potent inhibitor of monocyte/ macrophage activation (1,14,17,20,39). In polymorphonuclear neutrophils, IL-10 exerts its anti-inflammatory properties by downregulating functions such as NADPH oxidase activation and reactive oxygen species production (6).…”