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...

Human Skin in Organ Culture and Human Skin Cells (Keratinocytes and Fibroblasts) in Monolayer Culture for Assessment of Chemically Induced Skin Damage

“…The 2 cytokines could be detected in control skin organ cultures, and levels of both were increased in the presence of the two contactsensitizers examined. These data are consistent with previous findings from epidermal-equivalent or skin-equivalent cultures (Ponec and Kempenaar, 1995;Boxman et al, 1996; 700 VARANI ET AL.…”

Clonal characterization of fibroblasts in the superficial layer of the adult human dermis

“…Those fibroblasts that participate in wound repair would be expected to respond to this factor. IL-6 is an inflammatory cytokine that is produced by many different types of cells in skin, including dermal fibroblasts (Boxman et al 1993(Boxman et al , 1996. This factor regulates the differentiation of monocytes and plays a role in the communication of fibroblasts with epidermal cells; these events may include the regulation of epidermal cell proliferation and migration, both of which are features important for wound repair (Turksen et al 1992;Waelti et al 1992;Boxman et al 1993;Chomarat et al 2000;Gallucci et al 2004).…”

Global Gene Expression Analysis of Keloid Fibroblasts in Response to Electron Beam Irradiation Reveals the Involvement of Interleukin-6 Pathway

“…Generally, cytokines other than IL-6 play a role in the regulatory secretion of IL-6 through their interaction with keratinocytes, T cells, and the extracellular matrix. Autocrine regulation of IL-6 is affected by IL-6 itself and other pro-inflammatory factors (Maruyama et al, 1995;Boxman et al, 1996;Sporri et al, 1996). Some studies have shown that interferon (IFN)-g regulates IL-6 secretion from fibroblasts by stimulating the expression of MHC class II and CD40 (Mourad et al, 1992;Yellin et al, 1995).…”