Tomoki Chiba , Hidetoshi Inoko , Minoru Kimura and Takehito Sato * Role of nuclear I κ Bs in inflammation regulation

A wide variety of environmental cues, including inflammatory cytokines, ligands for pattern recognition receptors and endogenous danger signals, activate the inducible transcription factor nuclear factorκ B (NFκ B), which is a central regulator of inflammatory and immune responses. Excessive activation of NFκ B results in the development of severe diseases, such as chronic inflammatory disorders, autoimmune diseases and cancer. Therefore, the transcriptional activity of NFκ B is tightly regulated at multiple steps. One mechanism is mediated by the inhibitor of κ B (I κ B), a well-defined regulator of NFκ B that resides in the cytoplasm and prevents NFκ B from nuclear entry by sequestration. Recently, several atypical I κ Bs that reside in the nucleus were identified: Bcl-3, I κ B ζ , I κ BNS and I κ B η . In contrast to conventional I κ Bs, these atypical I κ Bs positively and negatively modulate NFκ B-mediated transcription. The function of atypical I κ Bs is independent of the prevention of NFκ B nuclear entry. Therefore, atypical I κ Bs are considered distinct from conventional I κ Bs and have been termed ‘ nuclear I κ Bs. ’ In addition to these members, our recent study indicated that I κ BL, originally reported as a susceptibility gene for rheumatoid arthritis, also serves as a nuclear I κ B. Biological and genetic studies strongly suggest that nuclear I κ Bs play important roles in the pathogenesis of inflammatory and autoimmune diseases via the regulation of both innate and adaptive immunity. In this review, we discuss the recent advances in our understanding of nuclear I κ Bs in the context of NFκ B-mediated transcriptional regulation and inflammatory responses.