Interleukin-1 induces transcription of keratin K6 in human epidermal keratinocytes

J Invest Dermatol. 2001 Feb;116(2):330-8. doi: 10.1046/j.1523-1747.2001.01249.x.

Abstract

Keratinocytes respond to injury by releasing the proinflammatory cytokine interleukin-1, which serves as the initial "alarm signal" to surrounding cells. Among the consequences of interleukin-1 release is the production of additional cytokines and their receptors by keratinocytes and other cells in the skin. Here we describe an additional effect of interleukin-1 on keratinocytes, namely the alteration in the keratinocyte cytoskeleton in the form of the induction of keratin 6 expression. Keratin 6 is a marker of hyperproliferative, activated keratinocytes, found in wound healing, psoriasis, and other inflammatory disorders. Skin biopsies in organ culture treated with interleukin-1 express keratin 6 in all suprabasal layers of the epidermis, throughout the tissue. In cultured epidermal keratinocytes, the induction of keratin 6 is time and concentration dependent. Importantly, only confluent keratinocytes respond to interleukin-1, subconfluent cultures do not. In the cells starved of growth factors, epidermal growth factor or tumor necrosis factor-alpha, if added simultaneously with interleukin-1, they synergistically augment the effects of interleukin-1. Using DNA-mediated cell transfection, we analyzed the molecular mechanisms regulating the keratin 6 induction by interleukin-1, and found that the induction occurs at the transcriptional level. We used a series of deletions and point mutations to identify the interleukin-1 responsive DNA element in the keratin 6 promoter, and determined that it contains a complex of C/EBP binding sites. The transcription factor C/EBPbeta binds this element in vitro, and the binding is augmented by pretreatment of the cells with interleukin-1. The interleukin-1 responsive element is clearly distinct from the epidermal growth factor responsive one, which means that the proinflammatory and proliferative signals independently regulate the expression of keratin 6. Thus, interleukin-1 initiates keratinocyte activation not only by triggering additional signaling events, but also by inducing directly the synthesis of keratin 6 in epidermal keratinocytes, and thus changing the composition of their cytoskeleton.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • Chromosome Mapping
  • Culture Media / pharmacology
  • Gene Expression Regulation / drug effects
  • Genes
  • HeLa Cells
  • Humans
  • Interleukin-1 / pharmacology*
  • Keratinocytes / metabolism*
  • Keratins / genetics*
  • Promoter Regions, Genetic
  • Skin / metabolism
  • Transcription, Genetic / drug effects

Substances

  • Culture Media
  • Interleukin-1
  • Keratins