title: Progranulin inhibits expression and release of chemokines CXCL9 and CXCL10 in a TNFR1 dependent manner.
abstract: Progranulin (PGRN), a pleiotrophic growth factor, is known to play an important role in the maintenance and regulation of the homeostatic dynamics of normal tissue development, proliferation, regeneration, and host-defense. PGRN also has potent anti-inflammatory functionality, and deregulated PGRN is associated with rheumatoid arthritis and inflammatory bowel disease. We have previously reported that PGRN directly binds to TNFR and significantly enhances Treg population and stimulates IL-10 production. To further investigate PGRN's function in the immune system we performed a gene array analysis on CD4+ T cells from wild type B6 mice and PGRN -/- mice. We identified many chemokines and their receptors, among which CXCL9 and CXCL10 were most prominent, that were significantly induced in PGRN null mice. Administration of recombinant PGRN protein strongly inhibited TNF and IFN-γ-induced CXCL9 and CXCL10 expression. In addition, CXCL9 expression is strongly upregulated in PGRN KO mice and its level is correlated with severity of inflammation in a dermatitis model. Further, we have demonstrated that PGRN-mediated inhibition of chemokine expression largely depends on TNFR1. Taken together, this study provides new insights into the mechanisms underlying PGRN mediated regulation of various inflammatory and autoimmune diseases.
authors.affiliation: Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY10003, USA.
authors.forename: Jyoti Joshi
authors.initials: JJ
authors.lastname: Mundra
authors.affiliation: Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY10003, USA.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Jian
authors.affiliation: Touro College of Medicine New York, New York 10016, USA.
authors.forename: Priyal
authors.initials: P
authors.lastname: Bhagat
authors.affiliation: Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY10003, USA.|Department of Cell Biology, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Chuan-Ju
authors.initials: CJ
authors.lastname: Liu
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000235:genetics* / Q000378:metabolism*; D054370:Chemokine CXCL9 / Q000235:genetics* / Q000378:metabolism*; D016000:Cluster Analysis; D003877:Dermatitis, Contact / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000077153:Progranulins; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins