One of the primary physiological roles of nuclear factor-kappa B (NF-κB) is in the immune system. In particular, NF-κB family members control the transcription of cytokines and antimicrobial effectors as well as genes that regulate cellular differentiation, survival and proliferation, thereby regulating various aspects of innate and adaptive immune responses. In addition, NF-κB also contributes to the development and survival of the cells and tissues that carry out immune responses in mammals. This review, therefore, describes the role of the NF-κB pathway in the development and functioning of the immune system.

NF-kappaB and the immune response.

The nuclear factor-κB (NF-κB) family of transcription factors is activated by canonical and non-canonical signalling pathways, which differ in both signalling components and biological functions Recent studies have revealed important roles for the non-canonical NF-κB pathway in regulating different aspects of immune functions Defects in non-canonical NF-κB signalling are associated with severe immune deficiencies, whereas dysregulated activation of this pathway contributes to the pathogenesis of various autoimmune and inflammatory diseases Here we review the signalling mechanisms and the biological function of the non-canonical NF-κB pathway We also discuss recent progress in elucidating the molecular mechanisms regulating non-canonical NF-κB pathway activation, which may provide new opportunities for therapeutic strategies

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The non-canonical NF-κB pathway in immunity and inflammation.

Disulfide bond formation is probably involved in the biogenesis of approximately one third of human proteins A central player in this essential process is protein disulfide isomerase or PDI PDI was the first protein-folding catalyst reported However, despite more than four decades of study, we still do not understand much about its physiological mechanisms of action This review examines the published literature with a critical eye This review aims to (a) provide background on the chemistry of disulfide bond formation and rearrangement, including the concept of reduction potential, before examining the structure of PDI; (b) detail the thiol-disulfide exchange reactions that are catalyzed by PDI in vitro, including a critical examination of the assays used to 2808determine them; (c) examine oxidation and reduction of PDI in vivo, including not only the role of ERo1 but also an extensive assessment of the role of glutathione, as well as other systems, such as peroxide, dehydroascorbate, and a d

Protein disulfide isomerase: a critical evaluation of its function in disulfide bond formation.

The immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) suppresses T-cell responses and promotes immune tolerance in mammalian pregnancy, tumour resistance, chronic infection, autoimmunity and allergic inflammation. 'Reverse signalling' and 'non-canonical activation' of the transcription factor nuclear factor-kappaB (NF-kappaB) characterize the peculiar events that occur in dendritic cells when T-cell-engaged ligands work as signalling receptors and culminate in the induction of IDO expression by dendritic cells in an inhibitor of NF-kappaB (IkappaB) kinase-alpha (IKKalpha)-dependent manner. In this Opinion article, we propose that IDO acts as a bridge between dendritic cells and CD4+ regulatory T cells, and that regulatory T cells use reverse signalling and non-canonical NF-kappaB activation for effector function and self-propagation. This mechanism may also underlie the protective function of glucocorticoids in pathological conditions.

IDO and regulatory T cells: a role for reverse signalling and non-canonical NF-κB activation

The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance.

Factors that determine the spectrum of target organs involved in autoimmune destruction are poorly understood. Although loss of function of autoimmune regulator (AIRE) in thymic epithelial cells is responsible for autoimmunity, the pathogenic roles of AIRE in regulating target-organ specificity remain elusive. In order to gain insight into this issue, we have established NOD mice, an animal model of type 1 diabetes caused by autoimmune attack against beta cell islets, in which Aire has been abrogated. Remarkably, acinar cells rather than beta cell islets were the major targets of autoimmune destruction in Aire-deficient NOD mice, and this alteration of intra-pancreatic target-organ specificity was associated with production of autoantibody against pancreas-specific protein disulfide isomerase (PDIp), an antigen expressed predominantly by acinar cells. Consistent with this pathological change, the animals were resistant to the development of diabetes. The results suggest that Aire not only is critical for the control of self-tolerance but is also a strong modifier of target-organ specificity through regulation of T cell repertoire diversification. We also demonstrated that transcriptional expression of PDIp was retained in the Aire-deficient NOD thymus, further supporting the concept that Aire may regulate the survival of autoreactive T cells beyond transcriptional control of self-protein expression in the thymus.

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Alteration of intra-pancreatic target-organ specificity by abrogation of Aire in NOD mice

IkappaB kinase (IKK) alpha exhibits diverse biological activities through protein kinase-dependent and -independent functions, the former mediated predominantly through a noncanonical NF-kappaB activation pathway. The in vivo function of IKKalpha, however, still remains elusive. Because a natural strain of mice with mutant NF-kappaB-inducing kinase (NIK) manifests autoimmunity as a result of disorganized thymic structure with abnormal expression of Rel proteins in the thymic stroma, we speculated that the NIK-IKKalpha axis might constitute an essential step in the thymic organogenesis that is required for the establishment of self-tolerance. An autoimmune disease phenotype was induced in athymic nude mice by grafting embryonic thymus from IKKalpha-deficient mice. The thymic microenvironment that caused autoimmunity in an IKKalpha-dependent manner was associated with defective processing of NF-kappaB2, resulting in the impaired development of thymic epithelial cells. Thus, our results demonstrate a novel function for IKKalpha in thymic organogenesis for the establishment of central tolerance that depends on its protein kinase activity in cooperation with NIK.

Shino Niki

Papers

Alteration of intra-pancreatic target-organ specificity by abrogation of Aire in NOD mice

Essential Role of IκB Kinase α in Thymic Organogenesis Required for the Establishment of Self-Tolerance