LPS Induced T(H)2 (Interleukin-4) Cytokine Production in Macrophages and Its Regulation

CYLD a deubiquitinase was recently reported to be a negative regulator of TLR2 signaling induced NF-kappaB activation via negative cross talk with TRAF6 and TRAF7. However the role of CYLD in LPS-TLR4 signaling, specifically in IL-4 production in 181 macrophages is yet to be determined. In this study we provide evidence that CYLD negatively regulates LPS induced IL4 but not TNF-alpha. Our data demonstrates for the first time that LPS induces CYLD in a TLR4, MyD88 and NF-kappaB dependent manner and this induction of CYLD is crucial in negatively regulating IL-4 production in macrophages. Our data suggest that CYLD interacts with MyD88 endogenously. The interaction attenuated the functional activity of MyD88 resulting in an inhibition of activation of IRAK-1. IRAK-1 inactivation in turn inhibited the phosphorylation of IkappaBalpha and thereby blocked NF-kappaB. NF-kappaB inactivation inhibited IL-4 production. The findings probe into the possible initial inhibition of LPS induced IL-4 production in macrophages and identifies a novel mechanism of CYLD action.