title: GILZ regulates Th17 responses and restrains IL-17-mediated skin inflammation.
abstract: Patients with inflammatory autoimmune diseases are routinely treated with synthetic glucocorticoids to suppress immunopathology. A crucial outcome of glucocorticoid exposure is induction of glucocorticoid-induced leucine zipper (GILZ), a protein with multiple functions that include inhibition of key immune cell signalling pathways. Here we report that GILZ maintains a threshold for activation of Th17 responses and IL-17-dependent pathology. GILZ expression was deficient in lesional skin of psoriasis patients and was negatively correlated with the pro-inflammatory cytokines IL-23, IL-17A and IL-22, and with STAT3 expression. Deficiency of GILZ in mice resulted in excessive inflammation and pro-inflammatory cytokine expression in the imiquimod model of psoriasis, and dendritic cells lacking GILZ produced greater IL-1, IL-23 and IL-6 in response to imiquimod stimulation in vitro. These cytokines stimulate Th17 cell differentiation, and we found unchallenged GILZ-deficient mice to have spontaneous production of IL-17A and IL-22 in vivo. We also identified a T cell-intrinsic role for GILZ in limiting Th17 cell formation in vitro in response to Th17-promoting cytokines IL-1β and IL-23. Addition of IL-6 under these conditions suppressed GILZ, allowing T cell proliferation and expression of Th17 genes, whereas exogenous delivery of GILZ using a cell-permeable fusion protein restored regulation of Th17 cell proliferation. Thus, GILZ has a non-redundant function to constrain pathogenic Th17 responses, with clinical implications for psoriasis.
authors.affiliation: Centre for Inflammatory Diseases, School of Clinical Sciences at Monash University, 246 Clayton Rd, Clayton, Melbourne 3168, Australia. Electronic address: sarah.a.jones@monash.edu.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Jones
authors.affiliation: Centre for Inflammatory Diseases, School of Clinical Sciences at Monash University, 246 Clayton Rd, Clayton, Melbourne 3168, Australia.
authors.forename: Diluptha N
authors.initials: DN
authors.lastname: Perera
authors.affiliation: Centre for Inflammatory Diseases, School of Clinical Sciences at Monash University, 246 Clayton Rd, Clayton, Melbourne 3168, Australia.
authors.forename: Huapeng
authors.initials: H
authors.lastname: Fan
authors.affiliation: Department of Microbiology and Immunology, The Doherty Institute at The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Brendan E
authors.initials: BE
authors.lastname: Russ
authors.affiliation: Centre for Inflammatory Diseases, School of Clinical Sciences at Monash University, 246 Clayton Rd, Clayton, Melbourne 3168, Australia.
authors.forename: James
authors.initials: J
authors.lastname: Harris
authors.affiliation: Centre for Inflammatory Diseases, School of Clinical Sciences at Monash University, 246 Clayton Rd, Clayton, Melbourne 3168, Australia.
authors.forename: Eric F
authors.initials: EF
authors.lastname: Morand
mesh_terms: D000634:Aminoquinolines / Q000276:immunology / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D003872:Dermatitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D000077271:Imiquimod; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011565:Psoriasis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; D016207:Cytokines; C498608:Dsip1 protein, mouse; D020381:Interleukin-17; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014157:Transcription Factors; D000077271:Imiquimod
keywords: GILZ; Glucocorticoid; Glucocorticoid-induced leucine zipper; IL-17; Psoriasis; Th17