title: Aspirin's Active Metabolite Salicylic Acid Targets High Mobility Group Box 1 to Modulate Inflammatory Responses.
abstract: Salicylic acid (SA) and its derivatives have been used for millennia to reduce pain, fever and inflammation. In addition, prophylactic use of acetylsalicylic acid, commonly known as aspirin, reduces the risk of heart attack, stroke and certain cancers. Because aspirin is rapidly de-acetylated by esterases in human plasma, much of aspirin's bioactivity can be attributed to its primary metabolite, SA. Here we demonstrate that human high mobility group box 1 (HMGB1) is a novel SA-binding protein. SA-binding sites on HMGB1 were identified in the HMG-box domains by nuclear magnetic resonance (NMR) spectroscopic studies and confirmed by mutational analysis. Extracellular HMGB1 is a damage-associated molecular pattern molecule (DAMP), with multiple redox states. SA suppresses both the chemoattractant activity of fully reduced HMGB1 and the increased expression of proinflammatory cytokine genes and cyclooxygenase 2 (COX-2) induced by disulfide HMGB1. Natural and synthetic SA derivatives with greater potency for inhibition of HMGB1 were identified, providing proof-of-concept that new molecules with high efficacy against sterile inflammation are attainable. An HMGB1 protein mutated in one of the SA-binding sites identified by NMR chemical shift perturbation studies retained chemoattractant activity, but lost binding of and inhibition by SA and its derivatives, thereby firmly establishing that SA binding to HMGB1 directly suppresses its proinflammatory activities. Identification of HMGB1 as a pharmacological target of SA/aspirin provides new insights into the mechanisms of action of one of the world's longest and most used natural and synthetic drugs. It may also provide an explanation for the protective effects of low-dose aspirin usage.
authors.affiliation: Boyce Thompson Institute for Plant Research, Ithaca, New York, United States of America.
authors.forename: Hyong Woo
authors.initials: HW
authors.lastname: Choi
authors.affiliation: Boyce Thompson Institute for Plant Research, Ithaca, New York, United States of America.
authors.forename: Miaoying
authors.initials: M
authors.lastname: Tian
authors.affiliation: Center of Advanced Biotechnology and Medicine, Department of Molecular Biology and Biochemistry, and Northeast Structural Genomics Consortium, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America.
authors.forename: Fei
authors.initials: F
authors.lastname: Song
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele University and Research Institute, Milano, Italy.
authors.forename: Emilie
authors.initials: E
authors.lastname: Venereau
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele University and Research Institute, Milano, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Preti
authors.affiliation: Boyce Thompson Institute for Plant Research, Ithaca, New York, United States of America.
authors.forename: Sang-Wook
authors.initials: SW
authors.lastname: Park
authors.affiliation: Center of Advanced Biotechnology and Medicine, Department of Molecular Biology and Biochemistry, and Northeast Structural Genomics Consortium, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America.
authors.forename: Keith
authors.initials: K
authors.lastname: Hamilton
authors.affiliation: Center of Advanced Biotechnology and Medicine, Department of Molecular Biology and Biochemistry, and Northeast Structural Genomics Consortium, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America.
authors.forename: G V T
authors.initials: GV
authors.lastname: Swapna
authors.affiliation: Boyce Thompson Institute for Plant Research, Ithaca, New York, United States of America.
authors.forename: Murli
authors.initials: M
authors.lastname: Manohar
authors.affiliation: Boyce Thompson Institute for Plant Research, Ithaca, New York, United States of America.
authors.forename: Magali
authors.initials: M
authors.lastname: Moreau
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele University and Research Institute, Milano, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Agresti
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele University and Research Institute, Milano, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gorzanelli
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele University and Research Institute, Milano, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: De Marchis
authors.affiliation: Center of Advanced Biotechnology and Medicine, Department of Molecular Biology and Biochemistry, and Northeast Structural Genomics Consortium, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America.
authors.forename: Huang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Chemical Biology, Department of Molecular Medicine, Cornell University, Ithaca, New York, United States of America.
authors.forename: Marc
authors.initials: M
authors.lastname: Antonyak
authors.affiliation: Boyce Thompson Institute for Plant Research, Ithaca, New York, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Micikas
authors.affiliation: Boyce Thompson Institute for Plant Research, Ithaca, New York, United States of America.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Gentile
authors.affiliation: Department of Chemistry and Chemical Biology, Department of Molecular Medicine, Cornell University, Ithaca, New York, United States of America.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Cerione
authors.affiliation: Boyce Thompson Institute for Plant Research, Ithaca, New York, United States of America.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Schroeder
authors.affiliation: Center of Advanced Biotechnology and Medicine, Department of Molecular Biology and Biochemistry, and Northeast Structural Genomics Consortium, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America.|Department of Biochemistry and Molecular Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America.
authors.forename: Gaetano T
authors.initials: GT
authors.lastname: Montelione
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele University and Research Institute, Milano, Italy.
authors.forename: Marco E
authors.initials: ME
authors.lastname: Bianchi
authors.affiliation: Boyce Thompson Institute for Plant Research, Ithaca, New York, United States of America.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Klessig
mesh_terms: D001241:Aspirin / Q000737:chemistry / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D024243:HMGB1 Protein / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D020156:Salicylic Acid / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D024243:HMGB1 Protein; D051546:Cyclooxygenase 2; D020156:Salicylic Acid; D001241:Aspirin