Keratins and the Keratinocyte Activation Cycle

Abstract

In wound healing and many pathologic conditions, keratinocytes become activated: they turn into migratory, hyperproliferative cells that produce and secrete extracellular matrix components and signaling polypeptides. At the same time, their cytoskeleton is also altered by the production of specific keratin proteins. These changes are orchestrated by growth factors, chemokines, and cytokines produced by keratinocytes and other cutaneous cell types. The responding intracellular signaling pathways activate transcription factors that regulate expression of keratin genes. Analysis of these processes led us to propose the existence of a keratinocyte activation cycle, in which the cells first become activated by the release of IL-1. Subsequently, they maintain the activated state by autocrine production of proinflammatory and proliferative signals. Keratins K6 and K16 are markers of the active state. Signals from the lymphocytes, in the form of Interferon-gamma, induce the expression of K17 and make keratinocytes contractile. This enables the keratinocytes to shrink the provisional fibronectin-rich basement membrane. Signals from the fibroblasts, in the form of TGF-beta, induce the expression of K5 and K14, revert the keratinocytes to the healthy basal phenotype, and thus complete the activation cycle.

Differential expression profiling of head and neck squamous carcinoma: significance in their phenotypic and biological classification

“…Paradoxically, Alevizos et al (2001) using oligonucleotide array reported a low expression of keratins 4 and 15 in HNSC. Our results are also supported by previous investigations of head and neck and other mucosa-derived squamous carcinomas in which upregulation of basal and proliferation-induced keratins were found (Freedberg et al, 2001;Mischke, 1998). The collective results suggest a potential diagnostic and biologic role for keratin expression in these tumors (Balm et al, 1996;Chu et al, 2001;Heyden et al, 1992;Ivanyi et al, 1990;Klijanienko et al, 1993;Mischke, 1998;Ogden et al, 1993).…”

Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients

“…The percentage of the total TGF-β activation (± SEM) was defined using an anti-TGF-β neutralizing antibody. *P < 0.05; **P < 0.001. link innate immune responses to subsequent adaptive immune responses, ultimately promoting wound repair (50). Thus, the induction of IL-1β that occurs during SM of the airway epithelium may act as both an autocrine factor to influence gene expression to facilitate cell migration and wound closure and as a paracrine factor to recruit inflammatory cells and to induce matrix production and contractility of adjacent fibroblasts (51,52).…”

Cortisol Synthesis in Epidermis Is Induced by IL-1 and Tissue Injury

“…Upon injury, keratinocytes are the first cells that respond (6,7) by releasing pre-stored interleukin-1 (IL-1) (8). IL-1 has an autocrine and a paracrine function; that is, to activate keratinocytes and to alert the surrounding cells and tissues.…”

“…The release of IL-1 by keratinocytes, with subsequent release of additional signaling molecules (9,10), demarcates the proinflammatory phase of wound healing. In response to these signals, activated keratinocytes start migrating and proliferating (7,8,11). Successful repair after tissue injury requires resolution of inflammatory response, transitioning keratinocyte (HEK) from activated to differentiating phenotype.…”