Integrity of IKK/NF‐κB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis

Abstract

A pathogenic connection between autoreactive T cells, fungal infection, and carcinogenesis has been demonstrated in studies of human autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) as well as in a mouse model in which kinase-dead Ikkα knock-in mice develop impaired central tolerance, autoreactive T cell-mediated autoimmunity, chronic fungal infection, and esophageal squamous cell carcinoma, which recapitulates APECED. IkB kinase α (IKKα) is one subunit of the IKK complex required for NF-kB activation. IKK/NF-kB is essential for central tolerance establishment by regulating the development of medullary thymic epithelial cells (mTECs) that facilitate the deletion of autoreactive T cells in the thymus. In this review, we extensively discuss the pathogenic roles of inborn errors in the IKK/NF-kB loci in the phenotypically related diseases APECED, immune deficiency syndrome, and severe combined immunodeficiency; differentiate how IKK/NF-kB components, through mTEC (stroma), T cells/leukocytes, or epithelial cells, contribute to the pathogenesis of infectious diseases, autoimmunity, and cancer; and highlight the medical significance of IKK/NF-kB in these diseases.

Attribution of NF-κB Activity to CHUK/IKKα-Involved Carcinogenesis

“…Moreover, an overexpressed K5.IKKα transgene partially regulates mTEC and central tolerance development [23,67]. Most likely, the biological impact of the specific K5 promoter-driven transgenic gene is earlier than the function of the K5 promoter-driven Cre on the central tolerance establishment during embryonic thymus development because the specific Cre takes two steps and the transgenic gene only takes one step to execute its biological activities.…”

Fish Collagen Peptides Enhance Thymopoietic Gene Expression, Cell Proliferation, Thymocyte Adherence, and Cytoprotection in Thymic Epithelial Cells via Activation of the Nuclear Factor-κB Pathway, Leading to Thymus Regeneration after Cyclophosphamide-Induced Injury

“…The adhesion experiments in this study revealed that FCPs increase the number of adherent thymocytes with TECs, which is accompanied by the increased expression of ICAM-1 and VCAM-1 in TECs, which is a crucial mechanism for thymocyte-TEC interactions that constitute important events in T-cell development through the activation of the NF-κB signaling pathway [61,74,95,96]. It is notable that both NF-κB and Wnt4 are associated with T-cell development [97,98]. However, it was discovered that they could act in a very different way.…”

“…However, it was discovered that they could act in a very different way. NF-κB plays a key role in regulating T-cell functions and development, while Wnt4 is involved in the regulation of age-related thymic involution [97,98]. Although the precise molecular mechanisms that underlie the relationship between NF-kB and Wnt4 in T-cell development are not yet fully understood, putative NF-kB/Rel binding sites have been identified at the Wnt4 enhancer region, suggesting that NF-kB signaling may directly regulate Wnt4 expression as an upstream regulator [99].…”

The Yin and Yang of IκB Kinases in Cancer

“…The NF-κB pathway, with its intricate family members, represents a dynamic signaling network that orchestrates cellular responses to a multitude of extracellular signals [13]. The fundamental aspect of this pathway revolves around the NF-κB transcription factors, comprising various members such as p65 (RelA), RelB, c-Rel, p105/p50, and p100/p52.…”