Transforming growth factor-α induces interleukin-6 in the human keratinocyte cell line HaCaT mainly by transcriptional activation

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Abstract

There is ample evidence that several cytokines, including transforming growth factor-alpha (TGF-α), interleukin (IL)-6, and IL-8 are upregulated in psoriasis, suggesting a pathogenic role for these cytokines. The sequence of these events, however, has not been elucidated. Recently it has been reported that TGF-α induces IL-6 in thymocytes through posttranscriptional regulation; therefore, we were interested in whether TGF-α can also induce IL-6 in human keratinocytes. Thus, we stimulated the human keratinocyte cell line HaCaT with TGF-α and tested supernatants for IL-6 activity. TGF-α resulted in a significant induction of the release of IL-6. This was also confirmed by northern blot analysis, which revealed a transient increase in IL-6 mRNA. This increase was unlikely due to enhanced mRNA stability, because we could not observe induction of IL-6-specific transcripts by TGF-α in the presence of actinomycin D. To determine whether IL-6 induction by TGF-α is transcriptionally regulated, we transfected fragments of the IL-6 upstream region, subcloned into a plasmid just upstream of the chloramphenicol acetyl transferase coding region, into HaCaT cells. A 238-bp fragment and a 123-bp fragment, both containing nuclear factor (NF)-IL-6 and NFκB sites, exhibited significant induction of chloramphenicol acetyl transferase activity upon treatment with TGF-α. Because IL-6 transcription is known to be regulated by activation of NFκB and NF-IL-6, we analyzed the activation of these DNA-binding proteins by electrophoretic mobility shift assays. NF-IL-6 binding to a 32P-labeled NF-IL-6 binding sequence was enhanced 20 min after TGF-α stimulation and returned to basal levels within 90 min, whereas NFκB binding activity was enhanced after 20 min and returned to normal 60 min after stimulation. We conclude that TGF-α induces IL-6 in HaCaT cells and, in contrast to thymocytes, may do so by transcriptional activation, possibly through activation of NFκB and NF-IL-6.

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Aragane, Y., Yamada, H., Schwarz, A., Pöppelmann, B., Luger, T. A., Tezuka, T., & Schwarz, T. (1996). Transforming growth factor-α induces interleukin-6 in the human keratinocyte cell line HaCaT mainly by transcriptional activation. Journal of Investigative Dermatology, 106(6), 1192–1197. https://doi.org/10.1111/1523-1747.ep12347985

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