Monocyte cd4o Signaling: Tyrosine Kinase Dependence and Il-4, Il-10 Downregulation

Document Type

Article

Publication Date

12-1-1996

Description

T cell activation of monocytes, such as occurs in nonseptic inflammatory responses, is mediated by both cytokine and cell contact-dependent signals. We have shown previously that CD4+ T cells can stimulate monocyte inflammatory cytokine production through contact-dependent mechanisms involving CD40, present on resting monocytes, and CD40 ligand (CD40L), expressed by activated T cells. Monocyte CD40 signaling was investigated using CD40-mediated activation of NF-κB and induction of IL-1β synthesis as readouts of monocyte activation. Monocytes were stimulated with a monoclonal anti-CD40 IgM, or with purified plasma membranes isolated from resting or activated CD4+ T cells. Prior to activation, monocytes were incubated with either with herbimycin A, a specific PTK inhibitor, or H-7, an inhibitor of PKC. Herbimycin A, but not H-7, blocked CD40-dependem IL-1β production. Sodium vanadate, a general phosphatase inhibitor, enhanced IL-1β production in response to anti-CD40, presumably through maintenance of PTK-initiated phosphorylation events. In addition herbimycin A, but not H-7, reduced antiCD40 activation of NF-κB in the monocytic cell line THP-1. Analysis of cytokine modulation of CD40 signaling revealed a dose-dependent downregulation of antiCD40 induced IL-1β synthesis with IL-4 and/or IL-10 preincubation. Cell surface expression of CD40 on monocytes was only slightly reduced with IL-4 or IL-10 treatment, indicating that IL-4 and IL-10 negate CD40 signaling through influences on components of the intracellular signaling pathway rather than at the level of CD40 surface expression.

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