Interleukin-1 receptor antagonist in normal and psoriatic epidermis.

Hammerberg, Craig; Arend, William P.; Fisher, Gary J.; Chan, Lawrence S.; Berger, Anna Maria Busse; Haskill, J. S.; Voorhees, John J.; Cooper, Kevin D.

doi:10.1172/jci115896

Cited by 123 publications

(76 citation statements)

References 65 publications

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“…calcium concentration in the medium, in subconfluent cultures of the HaCAT spontaneously transformed keratinocyte cell line, the icIL-1 Ra: IL-1 a ratio does not rise above 16. By contrast, confluent cultures of HaCAT cells produce less IL-la and have a higher iclL-lRa:IL-la ratio (248: 1), which is of a similar order of magnitude to that reported for normal skin in vivo [9]. Diflerentiating keratinocytes, as found in confluent cultures, have previously been reported to contain higher IL-IRa levels, and non-differentiated keratinocytes higher IL-ln levels [6].…”

Section: Discussionsupporting

confidence: 65%

“…The importance of assessing the IL-IRa ; IL-la ratio, rather than just the levels of the individual cytokines in isolation, is illustrated by recent studies on psoriasis. We and others [8,9] have documented reduced levels of ILIRa in lesional as opposed to involved skin from psoriasis patients. However, despite the reduction in keratinocyte IL-IRa inpsoriaticplaques.it has been reported that the IL-iRa: IL-la ratio in keratome skin biopsies is actually increased from 120:1 in normal skin to 1076:1 in psoriatic plaques, due to a diminution of IL-lrv levels [9].…”

Section: Introductionmentioning

confidence: 56%

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Modulation of the IL-1 cytokine network in keratinocytes by intracellular IL-1α and IL-1 receptor antagonist

Phillips

Feldmann

Breathnach

et al. 1995

Clinical and Experimental Immunology

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SUMMARYThe IL-I cytokine network in epidermal cells was studied in vitro, using the spontaneously transformed HaCAT human keratinocyte line. Intracellular (ic) IL-la and IL-1 receptor antagonist protein (IL-lRa) following cell lysis were readily identified assayed using a capture ELISA; whereas in culture supematants IL-lRa was not detected, and IL-Uv was present at only very low levels. Confiuent cultures of HaCAT cells were shown to provide optimal conditions for the study, since confluence increased the icIL-lRa: IL-la ratio to a level as seen in vivo, which was independent of Ca^ ^ concentration in the culture medium. The IL-lRa extracted from HaCAT cell lysates was functionally active, as demonstrated in the mouse thymocyte co-proliferation assay which could be blocked using a rabbit anti-IL-lRa antibody. Transforming growth factor-beta (TGF-/?1) stimulated a dose-dependent increase in HaCAT cell 1L-I(v without changing lL-lRa concentration, with a resultant reduction in the iclL-lRa: IL-IQ ratio from 320:1 to 100:1. Similarly. TGF-Q. interferon-gamma (IFN-7). IL-6, and tumour necrosis factor-alpha (TNF-a) substantially increased HaCAT cell IL-IQ, but had no efFect on the IL-IRa. with a concomitant reduction in theicIL-lRa: IL-la ratio. In contrast to their effects on monocytes, IL-4 and IL-IO at biologically active levels had no effect on IL-1«, IL-lRa or the icIL-lRa : IL-la ratio in confiuent HaCAT cells. Hydrocortisone reduced IL-ln to below the limit of sensitivity of the ELISA, and induced a small increase in IL-lRa of questionable biological significance. Thus, regulation ofthe IL-1 cytokine network in keratinocytes involves modulation of icIL lu rather than of icIL-lRa levels, and is markedly different from that noted in monocytes.

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Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 56%

Modulation of the IL-1 cytokine network in keratinocytes by intracellular IL-1α and IL-1 receptor antagonist

Phillips

Feldmann

Breathnach

et al. 1995

Clinical and Experimental Immunology

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“…The results of the present study show that it is unlikely that the decrease in IL-1 lev els is due to binding of IL-1 to an IL-l inhibitor [34], be cause the IL-1-inhibitor complex should have been detectëd in the RIA by the polyclonal antibody, which rec ognizes different epitopes on IL -la [20] and such a com plex should be TCA-precipitable. It is also unlikely that the decrease in IL-1 activity is caused by an increase in IL-1 receptor antagonist [35][36][37], since the reduction in the IL-1 bioactivity paralleled a decrease in IL-1 im munoreactivity. Furthermore, we can exclude the involve ment of extracellular degradation of IL-1 by proteolytic enzymes, since 125I-IL-1 was not degraded when incu bated in the presence of supernatants derived from IL -1 -stimulated fibroblast cultures.…”

Section: Discussionmentioning

confidence: 99%

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

Boxman

Ruwhof

Boerman

et al. 1996

Archives of Dermatological Research

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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...

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“…1-3), antagonist ligands [IL-1 receptor antagonist (IL-1ra); refs. [4][5][6], and both type 1 and type 2 IL-1 receptors (IL-1R1 and IL-1R2; refs. [7][8][9][10].…”

mentioning

confidence: 99%

“…This family of molecules binds to IL-1R1, but receptor occupancy by IL-1ra does not result in signal transduction (18). Thus, blockade of the IL-1R1 is an important means of limiting IL-1 activity (10,16,19), and under many circumstances, IL-1 gene expression appears to be paralleled by expression of the IL-1ra gene (5). The principal form of IL-1ra in keratinocytes is the intracellular IL-1ra, and it coexists in a cytoplasmic compartment with active preformed IL-1␣ in normal human and murine epidermis (6).…”

mentioning

confidence: 99%

Keratinocyte expression of the type 2 interleukin 1 receptor mediates local and specific inhibition of interleukin 1-mediated inflammation

Rauschmayr

Groves

Kupper

1997

Proc. Natl. Acad. Sci. U.S.A.

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Epidermal keratinocytes can express two types of interleukin 1 (IL-1) receptors: IL-1R1, which is active in signal transduction, and the less well characterized IL-1R2, which is incapable of transducing a signal and can be shed from cells. The binding of IL-1 in solution by IL-1R2 has been demonstrated, and it has been proposed to inhibit IL-1-mediated responses through this mechanism. We and others have reported that keratinocytes can be induced to express IL-1R2 both in vitro and in vivo, often under conditions that also favor IL-1 gene expression. We hypothesized that production of IL-1R2 by keratinocytes would be an efficient means to achieve local inhibition of IL-1-mediated responses without systemic consequences. To test this hypothesis, we have generated transgenic mice that constitutively express IL-1R2 on basal keratinocytes. Keratinocytes cultured from these animals shed the soluble form of the receptor into culture supernatants, and IL-1-inducible production of granulocyte͞macrophage colony-stimulating factor was markedly inhibited. In vivo, acute cutaneous vascular leakage, as well as chronic inf lammation induced by a well characterized IL-1-dependent stimulus, was significantly inhibited in IL-1R2 transgenic animals. In contrast, contact hypersensitivity was unaffected, suggesting that overexpression of IL-1R2 did not inhibit all types of inf lammation globally. Finally, systemic injection of IL-1 induced equivalent levels of plasma IL-6 in IL-1R2 transgenic and nontransgenic mice, suggesting that the activity of the transgenic IL-1R2 remained predominantly local and did not inf luence systemic IL-1 responses. We conclude that tissue-specific production of IL-1R2 can mediate IL-1 antagonism in tissue microenvironments without systemic consequences. Our transgenic mice may be a useful tool for determining the degree to which different types of cutaneous inf lammation depend on the IL-1 system.

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Interleukin-1 receptor antagonist in normal and psoriatic epidermis.

Cited by 123 publications

References 65 publications

Modulation of the IL-1 cytokine network in keratinocytes by intracellular IL-1α and IL-1 receptor antagonist

Modulation of the IL-1 cytokine network in keratinocytes by intracellular IL-1α and IL-1 receptor antagonist

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

Keratinocyte expression of the type 2 interleukin 1 receptor mediates local and specific inhibition of interleukin 1-mediated inflammation

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