title: TWEAK/Fn14 Signaling Involvement in the Pathogenesis of Cutaneous Disease in the MRL/lpr Model of Spontaneous Lupus.
abstract: Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK, TNFSF12) and its sole receptor Fn14, belonging to the TNF ligand and receptor superfamilies respectively, are involved in cell survival and cytokine production. The role of TWEAK/Fn14 interactions in the pathogenesis of cutaneous lupus has not been explored. TWEAK treatment of murine PAM212 keratinocytes stimulated the secretion of RANTES via Fn14 and promoted apoptosis. Parthenolide, but not wortmanin or the MAPK inhibitor PD98059, significantly decreased production of RANTES, indicating that this effect of TWEAK is mediated via NF-κB signaling. UVB irradiation significantly upregulated the expression of Fn14 on keratinocytes in vitro and in vivo and increased RANTES production. MRL/lpr Fn14 knockout (KO) lupus mice were compared with MRL/lpr Fn14 wild-type (WT) mice to evaluate for any possible differences in the severity of cutaneous lesions and the presence of infiltrating immune cells. MRL/lpr Fn14 KO mice had markedly attenuated cutaneous disease as compared with their Fn14 WT littermates, as evidenced by the well-maintained architecture of the skin and significantly decreased skin infiltration of T cells and macrophages. Our data strongly implicate TWEAK/Fn14 signaling in the pathogenesis of the cutaneous manifestations in the MRL/lpr model of spontaneous lupus and suggest a possible target for therapeutic intervention.
authors.affiliation: The Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Doerner
authors.affiliation: The Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wen
authors.affiliation: The Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Xia
authors.affiliation: The Division of Dermatology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Karin Blecher
authors.initials: KB
authors.lastname: Paz
authors.affiliation: The Division of Dermatology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: David
authors.initials: D
authors.lastname: Schairer
authors.affiliation: Biogen Idec, Cambridge, Massachusetts, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Wu
authors.affiliation: The Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Samantha A
authors.initials: SA
authors.lastname: Chalmers
authors.affiliation: Division of Rheumatology, NYU-Langone Medical Center, New York, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Izmirly
authors.affiliation: Jounce Therapeutics, Cambridge, Massachusetts, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Michaelson
authors.affiliation: Biogen Idec, Cambridge, Massachusetts, USA.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Burkly
authors.affiliation: The Division of Dermatology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Friedman
authors.affiliation: The Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA; The Division of Rheumatology, Albert Einstein College of Medicine, Bronx, NY, USA. Electronic address: chaim.putterman@einstein.yu.edu.
authors.forename: Chaim
authors.initials: C
authors.lastname: Putterman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D018946:Chemokine CCL5 / Q000378:metabolism; D000074049:Cytokine TWEAK; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism; D066298:In Vitro Techniques; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D008178:Lupus Erythematosus, Cutaneous / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000502:physiology* / Q000528:radiation effects; D015398:Signal Transduction / Q000502:physiology*; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000494:pharmacology / Q000502:physiology*; D014466:Ultraviolet Rays; D015854:Up-Regulation / Q000528:radiation effects
chemical_list: C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D000074049:Cytokine TWEAK; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors
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