Inflammatory Versus Proliferative Processes in Epidermis

Abstract

Epidermal keratinocytes respond to injury by becoming activated, i.e. hyperproliferative, migratory, and proinflammatory. These processes are regulated by growth factors and cytokines. One of the markers of activated keratinocytes is keratin K6. We used a novel organ culture system to show that tumor necrosis factor ␣ (TNF␣) induces the expression of K6 protein and mRNA in human skin. Multiple isoforms of K6 are encoded by distinct genes and have distinct patterns of expression. By having shown previously that proliferative signals, such as epidermal growth factor (EGF), induce expression of the cytoskeletal protein keratin K6b, we here demonstrate that the same isoform, K6b, is also induced by TNF␣, a proinflammatory cytokine. Specifically, TNF␣ induces the transcription of the K6b gene promoter. By using co-transfection, specific inhibitors, and antisense oligonucleotides, we have identified NFB and C/EBP␤ as the transcription factors that convey the TNF␣ signal. Both transcription factors are necessary for the induction of K6b by TNF␣ and act as a complex, although only C/EBP␤ binds the K6b promoter DNA. By using transfection, site-directed mutagenesis, and footprinting, we have mapped the site that responds to TNF␣, NFB, and C/EBP␤. This site is separate from the one responsive to EGF and AP1. Our results show that the proinflammatory (TNF␣) and the proliferative (EGF) signals in epidermis separately and independently regulate the expression of the same K6b keratin isoform. Thus, the cytoskeletal responses in epidermal cells can be precisely tuned by separate proliferative and inflammatory signals to fit the nature of the injuries that caused them.

Pathway-specific Profiling Identifies the NF-κB-dependent Tumor Necrosis Factor α-regulated Genes in Epidermal Keratinocytes

“…This agrees very well with the completely independently derived findings that NF-B indirectly regulates keratin gene expression (i.e. without binding to the keratin gene promoter DNAs) (43). In the case of keratin K6, NF-B and C/EBP␤ form a complex that binds to the C/EBP␤ consensus sequence motif in the promoter through the C/EBP␤ DNA binding domain (43).…”

“…without binding to the keratin gene promoter DNAs) (43). In the case of keratin K6, NF-B and C/EBP␤ form a complex that binds to the C/EBP␤ consensus sequence motif in the promoter through the C/EBP␤ DNA binding domain (43). This suggests indirect transcriptional regulation of epidermal markers by NF-B-containing complexes of transcription factors.…”

Activation of Extracellular Signal-Regulated Kinase Signaling by Epidermal Growth Factor Mediates c-Jun Activation and p300 Recruitment in Keratin 16 Gene Expression

“…The programmed expression of keratins, which is determined by the location and function of the keratinocytes within the epidermis, is commonly used as a phenotypic marker of epithelial development and differentiation (Fuchs, 1990). In the skin diseases characterized by hyperproliferation such as psoriasis, keratin 16 has been reported to be the marker in vivo and in vitro (Leigh et al, 1995;Komine et al, 2000). Therefore, keratin 16 is usually referred to as an activation-, hyperproliferation-, and disease-associated keratin.…”

Pseudomonas aeruginosaLipopolysaccharide Induction of Keratinocyte Proliferation, NF-κB, and Cyclin D1 Is Inhibited by Indomethacin

“…A variety of pathologic states in squamous tissue injury, including cholesteatoma, chronic burns, and aerodigestive carcinogenesis, are characterized by increased proliferation in response to stimuli that occur during chronic inflammation. One possible reason for this response is NF-B activation (5).…”