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

Rauschmayr, Tamara; Groves, Richard; Kupper, Thomas S.

doi:10.1073/pnas.94.11.5814

Cited by 91 publications

(66 citation statements)

References 38 publications

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“…9,34 IL-1R2 has the same inhibitory effect. 4,35 IL-1R1 ligation signals via the adaptor protein MyD88 to the kinases IRAK-2 and -4 and uses TRAF6 to involve NF-ĸB, p38, Janus kinase, and ERK for initiating the transcription of inflammatory cytokines including pro-IL-1a and pro-IL-1b. 4 Consequences of Inflammasome Activation or NLRP3/ASC Induction Other Than IL-1 Release Inflammasome activation also induces the secretion of mature IL-18 ( Figure 1).…”

Section: Il-1 Receptormentioning

confidence: 99%

Of Inflammasomes and Alarmins: IL-1β and IL-1α in Kidney Disease

Anders

2016

JASN

204

152

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Kidney injury implies danger signaling and a response by the immune system. The inflammasome is a central danger recognition platform that triggers local and systemic inflammation. In immune cells, inflammasome activation causes the release of mature IL-1b and of the alarmin IL-1a. Dying cells release IL-1a also, independently of the inflammasome. Both IL-1a and IL-1b ligate the same IL-1 receptor (IL-1R) that is present on nearly all cells inside and outside the kidney, further amplifying cytokine and chemokine release. Thus, the inflammasome-IL-1a/IL-b-IL-1R system is a central element of kidney inflammation and the systemic consequences. Seminal discoveries of recent years have expanded this central paradigm of inflammation. This review gives an overview of arising concepts of inflammasome and IL-1a/b regulation in renal cells and in experimental kidney disease models. There is a pipeline of compounds that can interfere with the inflammasome-IL-1a/IL-b-IL-1R system, ranging from recently described small molecule inhibitors of NLRP3, a component of the inflammasome complex, to regulatory agency-approved IL-1-neutralizing biologic drugs. Based on strong theoretic and experimental rationale, the potential therapeutic benefits of using such compounds to block the inflammasome-IL-1a/IL-b-IL-1R system in kidney disease should be further explored.

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Section: Il-1 Receptormentioning

confidence: 99%

Of Inflammasomes and Alarmins: IL-1β and IL-1α in Kidney Disease

Anders

2016

JASN

204

152

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“…Epidermal cell suspensions (ECS) were obtained by sequential dispase and trypsin digestion of split mouse ears as previously described (16). KC thus obtained were cultured on collagen-coated plates using nondifferentiating conditions with medium containing 0.05 mM Ca 2ϩ to allow maintenance of K14 expression.…”

Section: Epidermal Cell Culture and Il-23 Elisamentioning

confidence: 99%

“…In addition, epidermal sheets were prepared by dispase treatment of split mouse ears (16) and placed in normal culture medium. The total number of cells emigrating out of the sheets and the number of LC, identified by their veiled appearance, were counted under the hemocytometer at the time points indicated.…”

Section: Skin Organ Cultures and Epidermal Sheet Culturesmentioning

confidence: 99%

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IL-23 Production by Cosecretion of Endogenous p19 and Transgenic p40 in Keratin 14/p40 Transgenic Mice: Evidence for Enhanced Cutaneous Immunity

Kopp

Lenz

Bello-Fernández

et al. 2003

The Journal of Immunology

Self Cite

122

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p40, the common subunit of the proinflammatory cytokines IL-12 and IL-23, is produced by resident skin cells. Whereas the in vivo effects of IL-12 are well established, little is known about the role of IL-23 in cutaneous immune responses. In this study we show that p40 transgenic (TG) mice constitutively produce IL-23 (p19/p40), but not IL-12 (p35/p40), in basal keratinocytes by cosecretion of TG p40 with endogenous p19. Repeated injections of rIL-23 in littermate (LM) mice result in an inflammatory skin disease similar to that of p40 TG mice, confirming the proinflammatory activity of IL-23. Furthermore, IL-23 secretion by p40 TG keratinocytes induces elevated numbers of Langerhans cells (LC) with a marked up-regulation of costimulatory molecules, indicating advanced maturation of keratin 14 (K14)/p40 LC when compared with LM LC. At the functional level, freshly isolated K14/p40 LC greatly exceeded LC from LM animals in their capacity to stimulate allogeneic T cell proliferation. To assess whether IL-23 regulates cutaneous immune responses in vivo, we used an allogeneic skin transplantation model. Full thickness skin grafts from K14/p40 donors (H-2q) transplanted across a MHC class I and class II barrier onto BALB/c (H-2d) recipients were rejected in a significantly accelerated fashion (mean survival time: 8.8 days) when compared with skin grafts from non-TG LM (H-2q) (mean survival time: 10.7 days, p < 0.01). Based on these results we propose that IL-23-induced changes of LC may be an important mechanism in directing the outcome of cutaneous immune responses.

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“…IL-1RII ϩ chondrocytes (as a modified cartisel approach) may be significantly effective for cartilage repair when the transplanted chondrocytes and those in its vicinity may be protected against the insults of IL-1␤. This is further supported by the observation showing that transgene mice overexpressing IL-1RII in keratinocytes had a predominant effect locally and did not influence systemic IL-1␤ responses (44).…”

Section: Discussionmentioning

confidence: 60%

Functional Genomic Analysis of Type II IL-1β Decoy Receptor: Potential for Gene Therapy in Human Arthritis and Inflammation

Attur

Dave

Leung

et al. 2002

The Journal of Immunology

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Gene expression arrays show that human epithelial cells and human arthritis-affected cartilage lack detectable amounts of mRNA for IL-1 antagonizing molecules: IL-1Ra and IL-1RII, but constitutively express IL-1. Functional genomic analysis was performed by reconstituting human IL-1RII expression in various IL-1RII-deficient cell types to examine its antagonist role using gene therapy approaches. Adenovirus-expressing IL-1RII when transduced into human and bovine chondrocytes, human and rabbit synovial cells, human epithelial cells, and rodent fibroblasts expressed membrane IL-1RII and spontaneously released functional soluble IL-1RII. The IL-1RII+ (but not IL-1RII−) cells were resistant to IL-1β-induced, NO, PGE2, IL-6, and IL-8 production or decreased proteoglycan synthesis. IL-1RII inhibited the function of IL-1 in chondrocytes and IL-1- and TNF-α-induced inflammatory mediators in human synovial and epithelial cells. IL-1RII+ chondrocytes were more resistant to induction of NO and PGE2 by IL-1β compared with IL-1RII− cells incubated with a 10-fold (weight) excess of soluble type II IL-1R (sIL-1RII) protein. In cocultures, IL-1RII+ synovial cells released sIL-1RII, which in a paracrine fashion protected chondrocytes from the effects of IL-1β. Furthermore, IL-1RII+ (but not IL-1RII−) chondrocytes when transplanted onto human osteoarthritis-affected cartilage in vitro, which showed spontaneous release of sIL-1RII for 20 days, inhibited the spontaneous production of NO and PGE2 in cartilage in ex vivo. In summary, reconstitution of IL-1RII in IL-1RII− cells using gene therapy approaches significantly protects cells against the autocrine and paracrine effects of IL-1 at the signaling and transcriptional levels.

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

Cited by 91 publications

References 38 publications

Of Inflammasomes and Alarmins: IL-1β and IL-1α in Kidney Disease

Of Inflammasomes and Alarmins: IL-1β and IL-1α in Kidney Disease

IL-23 Production by Cosecretion of Endogenous p19 and Transgenic p40 in Keratin 14/p40 Transgenic Mice: Evidence for Enhanced Cutaneous Immunity

Functional Genomic Analysis of Type II IL-1β Decoy Receptor: Potential for Gene Therapy in Human Arthritis and Inflammation

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