title: Induction of Alternative Proinflammatory Cytokines Accounts for Sustained Psoriasiform Skin Inflammation in IL-17C+IL-6KO Mice.
abstract: IL-6 inhibition has been unsuccessful in treating psoriasis, despite high levels of tissue and serum IL-6 in patients. In addition, de novo psoriasis onset has been reported after IL-6 blockade in patients with rheumatoid arthritis. To explore mechanisms underlying these clinical observations, we backcrossed an established psoriasiform mouse model (IL-17C+ mice) with IL-6-deficient mice (IL-17C+KO) and examined the cutaneous phenotype. IL-17C+KO mice initially exhibited decreased skin inflammation; however, this decrease was transient and reversed rapidly, concomitant with increases in skin Tnf, Il36α/β/γ, Il24, Epgn, and S100a8/a9 to levels higher than those found in IL-17C+ mice. A comparison of IL-17C+ and IL-17C+KO mouse skin transcriptomes with that of human psoriasis skin revealed significant correlation among transcripts of skin of patients with psoriasis and IL-17C+KO mouse skin, and confirmed an exacerbation of the inflammatory signature in IL-17C+KO mice that aligns closely with human psoriasis. Transcriptional analyses of IL-17C+ and IL-17C+KO primary keratinocytes confirmed increased expression of proinflammatory molecules, suggesting that in the absence of IL-6, keratinocytes increase production of numerous additional proinflammatory cytokines. These preclinical findings may provide insight into why patients with arthritis being treated with IL-6 inhibitors develop new onset psoriasis and why IL-6 blockade for the treatment of psoriasis has not been clinically effective.
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Fritz
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Klenotic
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA; Ohio University, Heritage College of Osteopathic Medicine, Athens, Ohio, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Swindell
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA; Department of Dermatology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Zhi Qiang
authors.initials: ZQ
authors.lastname: Yin
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Groft
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Jaymie
authors.initials: J
authors.lastname: Baliwag
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Maya I
authors.initials: MI
authors.lastname: Camhi
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Doina
authors.initials: D
authors.lastname: Diaconu
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Young
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Foster
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Johnston
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Johann E
authors.initials: JE
authors.lastname: Gudjonsson
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA; Murdough Family Center for Psoriasis, Cleveland, Ohio, USA.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: McCormick
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA; Murdough Family Center for Psoriasis, Cleveland, Ohio, USA. Electronic address: nlw4@cwru.edu.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Ward
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation; D020381:Interleukin-17 / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics*; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011565:Psoriasis / Q000235:genetics* / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000473:pathology*
chemical_list: D016207:Cytokines; C515930:Il17c protein, mouse; D020381:Interleukin-17; D015850:Interleukin-6; C577686:interleukin-6, mouse