IKKα represses a network of inflammation and proliferation pathways and elevates c-Myc antagonists and differentiation in a dose-dependent manner in the skin

Abstract

Inhibitor of nuclear factor jB kinase-a (IKKa) is required for maintaining skin homeostasis and preventing skin tumorigenesis. However, its signaling has not been extensively investigated. In the present study, we generated two mouse lines that expressed different levels of transgenic IKKa in the basal epidermis under the control of keratin-5 promoter and further evaluated their effects on the major pathways of inflammation, proliferation, and differentiation in the skin. Regardless of the transgenic IKKa levels, the mice develop normally. Because IKKa deletion in keratinocytes blocks terminal differentiation and induces epidermal hyperplasia and skin inflammation, we depleted the endogenous IKKa in these transgenic mice and found that the transgenic IKKa represses epidermal thickness and induces terminal differentiation in a dose-dependent manner. Also, transgenic IKKa was found to elevate expression of Max dimer protein 1 (Mad1) and ovo-like 1, c-Myc antagonists, but repress activities of epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK), Jun-amino-terminal kinases, c-Jun, signal transducer and activator of transcription 3 (Stat3), and growth factor levels in a dose-dependent fashion in the skin. Moreover, EGFR reduction represses IKKa deletion-induced excessive ERK, Stat3 and c-Jun activities, and skin inflammation. These new findings indicate that elevated IKKa expression not only represses epidermal thickness and induces terminal differentiation, but also suppresses skin inflammation by an integrated loop. Thus, IKKa maintains skin homeostasis through a broad range of signaling pathways.

IKKα-mediated signaling circuitry regulates early B lymphopoiesis during hematopoiesis

“…It is possible that the remaining basal NF-B activity may be sufficient to protect the KA/KA B cells because IKK␤ and IKK␥ are present. In addition, we found increased Stat3 levels in KA/KA B cells, 37 which may contribute to BM B-cell survival.…”

Mouse Genetic Models Reveal Surprising Functions of IkB Kinase Alpha in Skin Development and Skin Carcinogenesis

“…Several studies have identified IKKα as a downstream target of p63 in epidermis formation [35,36,37]. Furthermore, IKKα has been shown to regulate the expression of Mad1, Mad2, and Ovol1 in keratinocyte proliferation and differentiation [6,7,38]. Because the defect in the embryonic skin development of Ikkα −/− mice has not been rescued by any of those genes described above, the genetic pathways IKKα-mediated in regulating embryonic development remain to be disclosed.…”

“…On the other hand, K5.IKKα transgenic mice develop normal skin, do not show any histological abnormalities, and rescue the skin phenotype of Ikkα −/− mice in an IKKα dose-dependent manner [38]. The transgenic IKKα has been shown to repress IKKα loss-induced the activities of epidermal growth factor receptor (EGFR), ERK, c-Jun N-terminal kinase (JNK), activator protein 1 (AP-1), and signal transducer and activator of transcription 3 (Stat3), and to elevate the expression of Ovol1 and Mad1, which are c-myc antagonists, in the skin of Ikkα −/− /K5.IKKα mice [38].…”

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

“…[105] K5 is highly and specifically expressed in mTECs and squamous epithelial cells. [25,106] We have shown that reintroduction of K5.IKKα restores NF-kB activities and mTEC numbers and abolishes inflammation and tumors in the skin and esophagus of Ikkα KA/KA mice. [23,25] Given that IKK/NF-kB activities are required for mTEC development, inactivation of NF-kB by overexpressed K5.mIkBα may impair mTEC development, resulting in autoreactive T cells and autoinflammation in mice.…”

“…It is known that IKKα reduction upregulates EGFR activity in keratinocytes. [19,106] Increased levels of inflammatory cytokines downregulate IKKα expression in human SCC cell lines. [23] Furthermore, increased fungal infection is associated with elevated PD-L1 expression in the esophageal epithelial cells and infiltrated macrophages.…”