Interleukin-10 signaling blocks inhibitor of kappa B kinase activity and nuclear factor kappa B DNA binding

The transcription factor nuclear factor kappa B (NF-kappa B) coordinates th e activation of numerous genes in response to pathogens and proinflammatory cytokines and is, therefore, pivotal in the development of acute and chron ic inflammatory diseases. In its inactive state, NF-kappa B is constitutive ly present in the cytoplasm as a p50-p65 heterodimer bound to its inhibitor y protein I kappa B, Proinflammatory cytokines, such as tumor necrosis fact or (TNF), activate NF-kappa B by stimulating the activity of the I kappa B kinases (IKKs) which phosphorylate I kappa B alpha on serine residues 32 an d 36, targeting it for rapid degradation by the 26 S proteasome, This enabl es the release and nuclear translocation of the NF-kappa B complex and acti vation of gene transcription. Interleukin-10 (IL-10) is a pleiotropic cytok ine that controls inflammatory processes by suppressing the production of p roinflammatory cytokines which are known to be transcriptionally controlled by NF-kappa B. Conflicting data exists on the effects of IL-10 on TNF- and LPS-induced NF-kappa B activity in human monocytes and the molecular mecha nisms involved have not been elucidated. In this study, we show that IL-10 functions to block NF-kappa B activity at two levels: 1) through the suppre ssion of IKK activity and 2) through the inhibition of NF-kappa B DNA bindi ng activity. This is the first evidence of an anti-inflammatory protein inh ibiting IKK activity and demonstrates that IKK is a logical target for bloc king inflammatory diseases.