Interleukin-1 induces transcription of keratin K6 in human epidermal keratinocytes.
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.
Komine
M
M
The Ronald O. Perelman Department of Dermatology, Department of Cell Biology and Biochemistry, New York University Medical Center, 550 First Avenue, New York, NY 10016, USA.
Rao
L S
LS
Freedberg
I M
IM
Simon
M
M
Milisavljevic
V
V
Blumenberg
M
M
D001483:Base Sequence; D002874:Chromosome Mapping; D003470:Culture Media / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005796:Genes; D006367:HeLa Cells; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D015603:Keratinocytes / Q000378:metabolism*; D007633:Keratins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012867:Skin / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D003470:Culture Media; D007375:Interleukin-1; D007633:Keratins