Opposing activities of two novel members of the IL-1 ligand family regulate skin inflammation

Blumberg, Hal; Dinh, Huyen; Trueblood, Esther S.; Pretorius, James K.; Kugler, David; Weng, Ning; Kanaly, Suzanne; Towne, Jennifer E.; Willis, Cynthia R.; Kuechle, Melanie K.; Sims, John E.; Peschon, Jacques J.

doi:10.1084/jem.20070157

Cited by 318 publications

(374 citation statements)

References 37 publications

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“…We cannot, as yet, say whether maturation of human DC subsets via IL-1Rrp2 and its ligands has an important role in vivo. However, in murine models of psoriasis, over-expression of IL-1F6 in murine basal keratinocytes (in an IL-1F5 −/− background) induces increased skin inflammation and both IL-1F6 and IL-1F5 are increased in human psoriatic skin [28]. Both IL-1F5 and IL-1F6 function via IL-1Rrp2 and this study may indicate that the consequence of IL-1Rrp2 expression and production of IL-1F6 has pro-inflammatory rather than anti-inflammatory effects, and studies which have shown that IL-1F6-, IL-1F8-and IL-1F9-induced nuclear translocation of NF-κB in epithelial cells [3] may also provide circumstantial evidence for this.…”

Section: Discussionmentioning

confidence: 99%

Expression of IL‐1Rrp2 by human myelomonocytic cells is unique to DCs and facilitates DC maturation by IL‐1F8 and IL‐1F9

et al. 2012

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We report for the first time that expression of the novel IL-1 cytokine receptor IL-1Rrp2 (IL-1R6) is unique to DCs within the human myelomonocytic lineage. IL-1Rrp2 was expressed by monocyte-derived dendritic cells (MDDCs) which was dose-dependently increased by IL-4 and correlated with increased numbers of differentiated MDDCs. Human plasmacytoid DCs also express IL-1Rrp2 but the receptor is not expressed by either myeloid DC type 1 (mDC1) or mDC2 cells. We also show that IL-1F8 or IL-1F9 cytokines, which signal through IL-1Rrp2, induce maturation of MDDCs, as measured by increased expression of HLA-DR and CD83 and decreased expression of CD1a. Furthermore, IL-1F8 stimulated increased CD40 and CD80 expression and IL-18 and IL-12 p70 production by MDDCs, which induced proliferation of IFN-γ-producing CD3 + lymphocytes (indicative of inflammatory Th1 subsets). IL-1F8 and IL-1F2 were equipotent in their ability to stimulate IL-18 secretion from MDDCs but IL-1F8 was not as potent as IL-1F2 in stimulating secretion of IL-12p70 from MDDCs or inducing lymphocyte proliferation Therefore, IL-1Rrp2 expression by some DC subsets may have an important function in the human immune response in vivo via its role in differentiation of inflammatory Th1 lymphocytes.Keywords: DC r IL-1F8 r IL-1F9 r IL-1Rrp2 IntroductionSix new members of the IL-1 family of cytokines have been described and named IL-1F5 to IL-1F10 (reviewed in [1]). However, to date, there have been very few reported studies of the biological effect of these cytokines. It has been shown that IL-1F9 activates NF-κB, in Jurkat cells, which over express IL-1 receptorrelated protein 2 (IL-1Rrp2, formerly IL-1R6) [2]. While Towne et al. [3] have reported that IL-1F5 antagonises this effect on NF-κB activation in epithelial cells stimulated with IL-1F6, IL-1F8 or IL-1F9 and that IL-F5 antagonist acts via IL-1Rrp2. Thus, the expression of IL-1Rrp2 is central to the functioning of Correspondence: Dr. Neil Foster e-mail: n.foster@nottingham.ac.uk these IL-1 family members. However, nothing is known about the expression of IL-1Rrp2 by human myeloid immune cells, although studies have reported that IL-1F7 is produced by human monocytes and, in a human natural killer cell line, IL-1F7 was shown to synergistically enhance inhibition of IL-1F4 (IL-18) by IL-18-binding protein; however, the expression of IL-1Rrp2 was not studied [4]. Human synovial fibroblasts and chondrocytes express IL-1Rrp2 and produce inflammatory mediators in response to stimulation by IL-1F8 [5], which indicates that expression of IL-1Rrp2 may have an important function during some human diseases. Classic members of the IL-1 family are important for the functioning of all human myeloid immune cells. These cytokines, IL-1α (IL-1F1), IL-1β (IL-1F2), IL-1 receptor antagonist (IL-1RA) (IL-1F3) and , are produced by and/or biologically affect myelomonocytic cells (monocytes, macrophages and DCs).www.eji-journal.eu 608Shilla Mutamba et al. Eur. J. Immunol. 2012. 42: 607-617 One such effect of classic IL-1 c...

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Section: Discussionmentioning

confidence: 99%

Expression of IL‐1Rrp2 by human myelomonocytic cells is unique to DCs and facilitates DC maturation by IL‐1F8 and IL‐1F9

et al. 2012

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“…There is now mounting evidence, from murine studies, that the IL-36R/IL-36α axis may have an important role in skin disorders [1][2][3]. This could also be the case in humans since missense mutations within IL-36RN genes, which encode for IL-36RA, an IL-36R antagonist, have been shown to be associated with pustular psoriasis [4].…”

Section: Introductionmentioning

confidence: 99%

IL-36 receptor is expressed by human blood and intestinal T lymphocytes and is dose–dependently activated via IL-36β and induces CD4+ lymphocyte proliferation

et al. 2016

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We show that IL-36R is expressed by T (CD4+ and CD8+) and B (CD19+) lymphocytes in human blood and also by CD4+ T lymphocytes in the intestinal lamina propria. IL-36R protein was mostly stored in the cytoplasm of CD4 lymphocytes and B cells, during steady andthe greatest expression of IL-36R mRNA was measured in CD4+ (T helper) lymphocytesIL-36 β, which functions via IL-36R induced rapid and significant (P <0.05) proliferation of CD4+ lymphocytes, within 48h. IL-36R expression was also maintained on the surface of circulating CD4+ lymphocytes which enter the intestinal lamina propria.In conclusion our study is the first to show that (1) all human blood lymphocytes express IL-36R; (2) IL-36R expression is maintained by circulating CD4+ lymphocytes which enter the intestinal lamina propria and (3) IL-36R/IL-36 β induces rapid CD4 lymphocyte proliferation. The possible significance of these results in the context of human disease is discussed.3

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“…In vitro analysis clarified that Il1f6 mRNA expression in epithelial cells could be induced by stimulation of the immune cells. Blumberg et al 27 reported that transgenic mice overexpressing dermal IL-1F6 showed acanthosis and increase in the number of macrophages and T-cells in these lesions; they also suggested that IL-1F6 controlled tissue injuries, promoting local inflammation. These findings strongly suggested that IL-1F6 in renal tubules was associated with local vicious cycles of tubulointerstitial inflammation.…”

Section: Il-1f6 In Mouse Models Of Renal Diseases O Ichii Et Almentioning

confidence: 99%

Local overexpression of interleukin-1 family, member 6 relates to the development of tubulointerstitial lesions

Ichii

Otsuka

Sasaki

et al. 2010

Laboratory Investigation

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Identification of factors that exacerbate a disease is important for the development of biomarkers. In this study, we discovered ectopic overexpression of interleukin-1 family, member-6 (IL-1F6) in several murine renal diseases. IL-1F6 participates in cytokine/chemokine production in the epithelium. In PCR array analysis for inflammatory mediators, Il1f6 showed the highest expression in the kidney of the B6.MRLc1 glomerulonephritis model. IL-1F6 was localized in the epithelium from the DCTs to CCDs, which showed tubular dilations or epithelial deciduations. Ultrastructual examination of the epithelial cells revealed that IL-1F6 was localized on the cytoplasmic ribosome, vesicles, and nucleus. In and around these tubules, we found infiltrations of CD3-positive T-cells and nestin-or a-smooth-muscle actin-positive mesenchymal cells. Expression of the IL-1F6 protein and Il1f6 mRNA in the kidney was increased by the development of TILs in the B6.MRLc1 model and in lupus (BXSB, NZB/WF1, and MRL/lpr), nephrotic syndrome (ICGN), and streptozotocin-induced diabetic models. IL-1F6 was also detected in the epithelia having squamous or deciduous contours in other organs such as the skin, esophagus, thymus, or uterus. In vitro analysis using M-1 cells from the murine collecting duct revealed that Il1f6 mRNA induction was related to the upregulation of IL-6, TGF-b receptor-1, and mesenchymal markers and to the downregulation of epithelial markers and changes in the squamous cells of the epithelium. Interestingly, urine Il1f6 mRNA expression was detected earlier than renal dysfunctions in these mouse models. Ectopic overexpression of IL-1F6 in kidneys is associated with TILs and especially with cell infiltrations and changes in epithelial morphology. We propose that local overexpression of IL-1F6 is related to the development of TILs.

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Opposing activities of two novel members of the IL-1 ligand family regulate skin inflammation

Cited by 318 publications

References 37 publications

Expression of IL‐1Rrp2 by human myelomonocytic cells is unique to DCs and facilitates DC maturation by IL‐1F8 and IL‐1F9

Expression of IL‐1Rrp2 by human myelomonocytic cells is unique to DCs and facilitates DC maturation by IL‐1F8 and IL‐1F9

IL-36 receptor is expressed by human blood and intestinal T lymphocytes and is dose–dependently activated via IL-36β and induces CD4+ lymphocyte proliferation

Local overexpression of interleukin-1 family, member 6 relates to the development of tubulointerstitial lesions

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