Fig. 7.

Schematic diagram of CD40-mediated suppression of TNF production. CD40 signal controls excessive TNF production by LPS-stimulated macrophages. First, CD40L on T cells stimulates CD40 on macrophages. On the other hand, LPS stimulates TLR4. CD40 signaling induces IRAK1 sumoylation in the presence of TRAF2 and intracellular isoform of osteopontin (iOPN). Sumoylation of IRAK1 allows its interaction with IRF5, which is activated by TLR4 signaling and works as an IRAK1 chaperone to the nucleus. Nuclear IRAK1 then binds to the Il10 promoter in macrophages. In an autocrine fashion, IL-10 activates IL-10R signaling, which destabilizes Tnfa mRNA. Therefore, dual signaling from CD40 and TLR4 are essential to control TNF in this mechanism.