title: Interleukin-17 cytokines are critical in development of fatal lupus glomerulonephritis.
abstract: Systemic lupus erythematosus is a potentially fatal autoimmune disease. Although interleukin-17 (IL-17) has been linked to human lupus and mouse models of this disease, it has not been addressed whether this cytokine plays a critical role in fatal lupus pathology. Here we have demonstrated that increased production of IL-17 cytokines and their signaling via the adaptor protein CIKS (a.k.a. Traf3ip2, Act1) critically contributed to lethal pathology in an FcgammaR2b-deficient mouse model of lupus. Mice lacking IL-17 and especially those lacking CIKS showed greatly improved survival and were largely protected from development of glomerulonephritis. Importantly in this model, potential effects of IL-17 cytokines on antibody production could be distinguished from critical local contributions in kidneys, including recruitment of neutrophils and monocytes. These findings provide the proof of principle that signaling by IL-17 family cytokines mediated via CIKS presents promising therapeutic targets for the treatment of systemic lupus erythematosus, especially in cases with kidney involvement.
authors.affiliation: Immune Activation Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Prapaporn
authors.initials: P
authors.lastname: Pisitkun
authors.forename: Hye-Lin
authors.initials: HL
authors.lastname: Ha
authors.forename: Hongshan
authors.initials: H
authors.lastname: Wang
authors.forename: Estefania
authors.initials: E
authors.lastname: Claudio
authors.forename: Caitlyn C
authors.initials: CC
authors.lastname: Tivy
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
authors.forename: Tanya N
authors.initials: TN
authors.lastname: Mayadas
authors.forename: Gabor G
authors.initials: GG
authors.lastname: Illei
authors.forename: Ulrich
authors.initials: U
authors.lastname: Siebenlist
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004195:Disease Models, Animal; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism; D050533:Glomerular Basement Membrane / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000502:physiology*; D007668:Kidney / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics; D053722:Receptors, Interleukin-17 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001323:Autoantibodies; C499172:Fcgr2b protein, mouse; D020381:Interleukin-17; D017452:Receptors, IgG; D053722:Receptors, Interleukin-17; C515963:Traf3ip2 protein, mouse