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

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 modu lated by their mutual interaction, and thereby 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 subsequent internalization and intracellular degrada tion is the most likely mechanism involved in the re duction 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 di rectly related to the number of IL-1 receptors found on these cell types. In conclusion, these results indicate that the release of IL -la 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 re sponse. The amounts of both cytokines produced by fi broblasts were at least two to three orders of magni tude higher than those produced by keratinocytes, suggesting an important role of fibroblasts in the gen eral inflammatory response. Furthermore, fibroblasts might be involved in turning off this inflammatory re sponse by reducing IL-1 levels, most likely via IL-1 rewere induced by IL -la . The IL -la-induced increase in ceptor-mediated uptake. IL-8 and IL-6 production, both on the protein level as well as on the mRNA level, were concentration depen dent and occurred almost simultaneously. W hile the induction of IL-6 and IL-8 occurred simultaneously, the IL-6 mRNA remained elevated for longer. In con-------------------trast to increased IL-6 and IL-8 production the I L -la IntroductionKey words Interleukin-8 ■ Interleukin-1 ♦ IL-l receptor ratinoeyte -Fibroblast interaction levels markedly decreased upon culturing o f fibro blasts in keratinocyte-derived conditioned medium. rr h e r e is increasing evidence that the release and producFrom internalization experiments it could be con-tion of cytokines, either preformed o.r newly synthesized, eluded that binding of IL-1 to IL-1 receptors, and its by keratinocytes and fibroblasts is altered after certain events, such as skin injury [I], The keratinocytes become 'activated1 and release, amongst other things, the proin flammatory cytokine interleukin-1 (IL-1) |2 |. It has been shown that exposure of skin cells to IL-l leads to an in creased production...

Phospholipid Scramblase 1 Is Secreted by a Lipid Raft-dependent Pathway and Interacts with the Extracellular Matrix Protein 1 in the Dermal Epidermal Junction Zone of Human Skin

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Comparison of the concentration of salivary IL8 in patients with oral squamous cell carcinoma and healthy subjects

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