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Role of fibroblasts in the regulation of proinflammatory interleukin IL-1, IL-6 and IL-8 levels induced by keratinocyte-derived IL-1

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Abstract

In the epidermis, the keratinocytes are the first cells to be encountered by external stimuli and they are able to promote the inflammatory response by increased production and release of various cytokines. In their turn, these cytokines may directly affect the production of proinflammatory cytokines in human dermal fibroblasts. In addition, in both epithelial and mesenchymal cells cytokine production may be modulated by their mutual interaction, and therapy regulate the inflammatory response. The present study aimed to examine the role of fibroblasts in the regulation of proinflammatory IL-1, IL-6 and IL-8 levels induced by keratinocyte-derived IL-1. The data, show that in fibroblasts exposed to conditioned media derived from cultures of normal human keratinocytes or squamous carcinoma cells (SCC-4), both the IL-8 and IL-6 mRNA expression as well as protein production were elevated. In addition, it was shown that these effects were induced by IL-1α. The IL-1α-induced increase in IL-8 and IL-6 production, both on the protein level as well as on the mRNA level, were concentration dependent and occurred almost simultaneously. White the induction of IL-6 and IL-8 occurred simultaneously, the IL-6 mRNA remained elevated for longer. In contrast to increased IL-6 and IL-8 production the IL-1α levels markedly decreased upon culturing of fibroblasts in keratinocyte-derived conditioned medium. From internalization experiments it could be concluded that binding of IL-1 to IL-1 receptors and its subsequent internalization and intracellular degradation is the most likely mechanism involved in the reduction of IL-1 levels by fibroblasts. Comparing the rate of IL-1 reduction in the presence of various cell types indicated that the rate of IL-1 reduction is directly related to the number of IL-1 receptors found on these cell types. In conclusion, these results indicate that the release of IL-1α by activated keratinocytes may act as an inducer of IL-8 and IL-6 production in neighbouring fibroblasts. This may be an important pathway for the amplification of the inflammatory response. The amounts of both cytokines produced by fibroblasts were at least two to three orders of magnitude higher than those produced by kerationocytes, suggesting an important role of firoblasts in the general inflammatory response. Furthermore, fibroblasts might be involved in turning off this inflammatory response by reducing IL-1 levels, most, likely via IL-1 receptor-mediated uptake.

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Authors and Affiliations

  1. Department of Dermatology, University Hospital Leiden, P.O. Box 9600, 2300 RC, Leiden, The Netherlands

    Ingeborg L. A. Boxman, Cindy Ruwhof & Maria Ponec

  2. Department of Endocrinology, University of Hospital Leiden, Leiden, The Netherlands

    Ingeborg L. A. Boxman & Clemens W. G. M. Löwik

  3. Deparmtment of Nuclear Medicine, University Hospital Nijmegen, Nijmegen, The Netherlands

    Otto C. Boerman

Authors
  1. Ingeborg L. A. Boxman
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  2. Cindy Ruwhof
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  3. Otto C. Boerman
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  4. Clemens W. G. M. Löwik
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  5. Maria Ponec
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Boxman, I.L.A., Ruwhof, C., Boerman, O.C. et al. Role of fibroblasts in the regulation of proinflammatory interleukin IL-1, IL-6 and IL-8 levels induced by keratinocyte-derived IL-1. Arch Dermatol Res 288, 391–398 (1996). https://doi.org/10.1007/BF02507108

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  • DOI: https://doi.org/10.1007/BF02507108

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