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Nitroalkenes Suppress Lipopolysaccharide-Induced Signal Transducer and Activator of Transcription Signaling in Macrophages: A Critical Role of Mitogen-Activated Protein Kinase Phosphatase 1

Cardiovascular Medicine (T.I., T.C., J.Z., K.C., Y.E.C.), University of Michigan Medical Center, Ann Arbor, Michigan 48109; Department of Cell and Developmental Biology and Anatomy (T.I., T.C.), University of South Carolina, Columbia, South Carolina 29208; Children’s Research Institute (Y.L.), Columbus Children’s Hospital, Department of Pediatrics, The Ohio State University, Columbus, Ohio 43205; and Department of Pharmacology (F.J.S., P.R.S.B., B.A.F.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Address all correspondence and requests for reprints to: Dr. Bruce Freeman, Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261. E-mail: freerad{at}pitt.edu; or Dr. Yuqing E. Chen, Cardiovascular Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109. E-mail: echenum{at}umich.edu; or Dr. Taixing Cui, Department of Cell and Developmental Biology and Anatomy, University of South Carolina, Columbia, South Carolina 29208. E-mail: tcui{at}gw.med.sc.edu.

Nitration products of unsaturated fatty acids are formed via NO-dependent oxidative reactions and appear to be a new class of endogenous antiinflammatory mediators. Nitroalkene derivatives of nitrated linoleic acid (LNO₂) and nitrated oleic acid (OA-NO₂) alleviate inflammatory responses in macrophages, but the underlying mechanisms remain to be fully defined. Herein we report that LNO₂ and OA-NO₂ suppress proinflammatory signal transducer and activator of transcription (STAT) signaling in macrophages. In RAW264.7 cells, a murine macrophage cell line, LNO₂ and OA-NO₂ inhibited the lipopolysaccharide (LPS)-induced STAT1 phosphorylation and the STAT1-dependent transcriptional activity, thereby suppressing expression of its target gene such as iNOS and MCP-1. The nitroalkene-mediated inhibition of STAT1 activity was not affected by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (a NO scavenger), GW9662 (a peroxisome proliferator-activated receptor--specific antagonist) or glutathione (an antioxidant), suggesting an underlying mechanism independent of NO, peroxisome proliferator-activated receptor-, or thio-nitralkylation. In contrast, LNO₂ or OA-NO₂ alone up-regulated both mRNA and protein levels of MAPK phosphatase 1 (MKP-1) and strongly augmented the LPS-induced MKP-1 protein expression. Knockdown of MKP-1 by MKP-1 small interfering RNA enhanced the LPS-induced STAT1 phosphorylation, suggesting that MKP-1 acts as a negative regulator for LPS-induced STAT signaling. In addition, the nitroalkene-mediated inhibitory effects on STAT1 phosphorylation, iNOS expression, and MCP-1 secretion were also largely attenuated by the MKP-1 small interfering RNA approach. Taken together, our data demonstrate that nitroalkenes inhibit proinflammatory STAT signaling through inducting MKP-1 in macrophages.