Stanniocalcin-1 suppresses superoxide generation in macrophages through induction of mitochondrial UCP2

• Published in: Journal of leukocyte biology Vol. 86; no. 4; pp. 981 - 988
• Main Authors: Wang, Yanlin, Huang, Luping, Abdelrahim, Maen, Cai, Qingsong, Truong, Anh, Bick, Roger, Poindexter, Brian, Sheikh‐Hamad, David
• Format: Journal Article
• Language: English
• Published: United States Society for Leukocyte Biology 01.10.2009; The Society for Leukocyte Biology
• Subjects: Adenosine Triphosphate - genetics; Adenosine Triphosphate - immunology; Animals; apoptosis; Apoptosis - genetics; Apoptosis - immunology; Cell Line; Cell Movement - genetics; Cell Movement - immunology; Electron Transport - immunology; free radicals; G1 Phase - genetics; G1 Phase - immunology; Gene Expression Regulation - genetics; Gene Expression Regulation - immunology; gene regulation; Glycoproteins - genetics; Glycoproteins - immunology; Inflammation, Extracellular Mediators, & Effector Molecules; Ion Channels - genetics; Ion Channels - immunology; lipopolysaccharide; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - pathology; Membrane Glycoproteins - genetics; Membrane Glycoproteins - immunology; Mice; Mice, Knockout; Mitochondria - genetics; Mitochondria - immunology; Mitochondrial Proteins - genetics; Mitochondrial Proteins - immunology; monocytes; NADPH Oxidase 2; NADPH Oxidases - genetics; NADPH Oxidases - immunology; Necrosis - genetics; Necrosis - immunology; Protein Transport - genetics; Protein Transport - immunology; Superoxides - immunology; Time Factors; Uncoupling Protein 2; uncoupling proteins
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1189/jlb.0708454

Mammalian stanniocalcin‐1, a secreted phosphogylcoprotein that targets the mitochondria, suppresses superoxide and may function as an LPS antagonist in macrophages. Mammalian STC1 decreases the mobility of macrophages and diminishes their response to chemokines. In the current experiments, we sought to determine the impact of STC1 on energy metabolism and superoxide generation in mouse macrophages. STC1 decreases ATP level in macrophages but does not affect the activity of respiratory chain complexes I–IV. STC1 induces the expression of mitochondrial UCP2, diminishing mitochondrial membrane potential and superoxide generation; studies in UCP2 null and gp91phox null macrophages suggest that suppression of superoxide by STC1 is UCP2‐dependent yet is gp91phox‐independent. Furthermore, STC1 blunts the effects of LPS on superoxide generation in macrophages. Exogenous STC1 is internalized by macrophages within 10 min and localizes to the mitochondria, suggesting a role for circulating and/or tissue‐derived STC1 in regulating macrophage function. STC1 induces arrest of the cell cycle at the G1 phase and reduces cell necrosis and apoptosis in serum‐starved macrophages. Our data identify STC1 as a key regulator of superoxide generation in macrophages and suggest that STC1 may profoundly affect the immune/inflammatory response.