title: Opposing activities of two novel members of the IL-1 ligand family regulate skin inflammation.
abstract: The interleukin (IL)-1 family members IL-1alpha, -1beta, and -18 are potent inflammatory cytokines whose activities are dependent on heterodimeric receptors of the IL-1R superfamily, and which are regulated by soluble antagonists. Recently, several new IL-1 family members have been identified. To determine the role of one of these family members in the skin, transgenic mice expressing IL1F6 in basal keratinocytes were generated. IL1F6 transgenic mice exhibit skin abnormalities that are dependent on IL-1Rrp2 and IL-1RAcP, which are two members of the IL-1R family. The skin phenotype is characterized by acanthosis, hyperkeratosis, the presence of a mixed inflammatory cell infiltrate, and increased cytokine and chemokine expression. Strikingly, the combination of the IL-1F6 transgene with an IL1F5 deficiency results in exacerbation of the skin phenotype, demonstrating that IL-1F5 has antagonistic activity in vivo. Skin from IL1F6 transgenic, IL1F5(-/-) pups contains intracorneal and intraepithelial pustules, nucleated corneocytes, and dilated superficial dermal blood vessels. Additionally, expression of IL1RL2, -1F5, and -1F6 is increased in human psoriatic skin. In summary, dysregulated expression of novel agonistic and antagonistic IL-1 family member ligands can promote cutaneous inflammation, revealing potential novel targets for the treatment of inflammatory skin disorders.
authors.affiliation: Department of Inflammation, 2Department of Pathology, 3Department of Biostatistics, Amgen, Seattle, WA 98119, USA. blumberh@amgen.com
authors.forename: Hal
authors.initials: H
authors.lastname: Blumberg
authors.forename: Huyen
authors.initials: H
authors.lastname: Dinh
authors.forename: Esther S
authors.initials: ES
authors.lastname: Trueblood
authors.forename: James
authors.initials: J
authors.lastname: Pretorius
authors.forename: David
authors.initials: D
authors.lastname: Kugler
authors.forename: Ning
authors.initials: N
authors.lastname: Weng
authors.forename: Suzanne T
authors.initials: ST
authors.lastname: Kanaly
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Towne
authors.forename: Cynthia R
authors.initials: CR
authors.lastname: Willis
authors.forename: Melanie K
authors.initials: MK
authors.lastname: Kuechle
authors.forename: John E
authors.initials: JE
authors.lastname: Sims
authors.forename: Jacques J
authors.initials: JJ
authors.lastname: Peschon
mesh_terms: D000818:Animals; D016667:Bacterial Capsules; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D007375:Interleukin-1 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D011135:Polysaccharides, Bacterial / Q000235:genetics; D011401:Promoter Regions, Genetic; D012867:Skin / Q000473:pathology; D012871:Skin Diseases / Q000503:physiopathology*
chemical_list: C508586:IL36A protein, human; D007375:Interleukin-1; D008024:Ligands; D011135:Polysaccharides, Bacterial; C039514:capsular polysaccharide K14