title: Adipocyte-derived PAMM suppresses macrophage inflammation by inhibiting MAPK signalling.
abstract: Macrophages within adipose tissue play a key role in mediating inflammatory responses in adipose tissue that are associated with obesity-related metabolic complications. In an effort to identify novel proteins secreted from adipocytes that may negatively regulate macrophage inflammation, we found that peroxiredoxin (PRX)-like 2 activated in M-CSF stimulated monocytes (PAMM), a CXXC-type PRX-like 2 domain-containing redox regulatory protein, is a novel secreted protein with potent anti-inflammatory properties. PAMM is secreted from mature human adipocytes but not preadipocytes. Overexpression of PAMM significantly attenuated lipopolysaccharide (LPS)-induced macrophage inflammation. Incubation of macrophages with adipocyte-conditional medium treated with anti-PAMM antibody significantly enhanced LPS-induced interleukin-12 (IL-12) expression in Raw264.7 cells. In addition, incubation of Raw264.7 cells with purified PAMM protein had a similar anti-inflammatory effect. Moreover, forced expression of PAMM in Raw264.7 cells resulted in decreased LPS-induced ERK1/2, p38 and c-Jun N-terminal kinase (JNK) phosphorylation, suggesting that PAMM exerted the anti-inflammatory function probably by suppressing the mitogen-activated protein kinase (MAPK) signalling pathway. Mutations in the CXXC motif of PAMM that suppressed its anti-redox activity were still able to suppress production of inflammatory cytokines in LPS-stimulated macrophages, suggesting that PAMM's anti-inflammatory properties may be independent of its antioxidant properties. Finally, PAMM was highly expressed in both white (WAT) and brown adipose tissues (BAT) and further increased in obesity status. Our results suggest that adipocyte-derived PAMM may suppress macrophage activation by inhibiting MAPK signalling pathway.
authors.affiliation: Department of Pathophysiology, The Institute of Cardiovascular Disease, University of South China, Hengyang, Hunan 421001, China Department of Basic Medical Science, School of Medicine, University of Missouri Kansas City, Kansas City, MO 64108, U.S.A.
authors.forename: Fang
authors.initials: F
authors.lastname: Guo
authors.affiliation: Department of Pathophysiology, The Institute of Cardiovascular Disease, University of South China, Hengyang, Hunan 421001, China Department of Basic Medical Science, School of Medicine, University of Missouri Kansas City, Kansas City, MO 64108, U.S.A.
authors.forename: Hui
authors.initials: H
authors.lastname: He
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi 330031, China.
authors.forename: Zhi-Chao
authors.initials: ZC
authors.lastname: Fu
authors.affiliation: Department of Basic Medical Science, School of Medicine, University of Missouri Kansas City, Kansas City, MO 64108, U.S.A.
authors.forename: Shengping
authors.initials: S
authors.lastname: Huang
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi 330031, China.
authors.forename: Tingtao
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Basic Medical Science, School of Medicine, University of Missouri Kansas City, Kansas City, MO 64108, U.S.A.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Papasian
authors.affiliation: Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA 02115, U.S.A.
authors.forename: Leslie R
authors.initials: LR
authors.lastname: Morse
authors.affiliation: Department of Mineralized Tissue Biology, The Forsyth Institute, Cambridge, MA 02142, U.S.A.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Mineralized Tissue Biology, The Forsyth Institute, Cambridge, MA 02142, U.S.A.
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Battaglino
authors.affiliation: Cardiovascular Research Center, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, U.S.A.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Yang
authors.affiliation: Department of Pathophysiology, The Institute of Cardiovascular Disease, University of South China, Hengyang, Hunan 421001, China fum@umkc.edu hongbo.xin@yahoo.com zsjiang2005@163.com.
authors.forename: Zhisheng
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi 330031, China fum@umkc.edu hongbo.xin@yahoo.com zsjiang2005@163.com.
authors.forename: Hong-Bo
authors.initials: HB
authors.lastname: Xin
authors.affiliation: Department of Basic Medical Science, School of Medicine, University of Missouri Kansas City, Kansas City, MO 64108, U.S.A. fum@umkc.edu hongbo.xin@yahoo.com zsjiang2005@163.com.
authors.forename: Mingui
authors.initials: M
authors.lastname: Fu
mesh_terms: D017667:Adipocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020816:Amino Acid Motifs; D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D054464:Peroxiredoxins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; C555780:PAMM protein, mouse; C555781:PRXL2A protein, human; D054464:Peroxiredoxins; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4
keywords: adipocyte; anti-inflammation; macrophage; peroxiredoxin-like 2 activated in M-CSF-stimulated monocytes (PAMM); redox; secreted protein