title: TIPE2 negatively regulates inflammation by switching arginine metabolism from nitric oxide synthase to arginase.
abstract: TIPE2, the tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 (TNFAIP8L2), plays an essential role in maintaining immune homeostasis. It is highly expressed in macrophages and negatively regulates inflammation through inhibiting Toll-like receptor signaling. In this paper, we utilized RAW264.7 cells stably transfected with a TIPE2 expression plasmid, as well as TIPE2-deficient macrophages to study the roles of TIPE2 in LPS-induced nitric oxide (NO) and urea production. The results showed that TIPE2-deficiency significantly upregulated the levels of iNOS expression and NO production in LPS-stimulated macrophages, but decreased mRNA levels of arginase I and urea production. However, TIPE2 overexpression in macrophages was capable of downregulating protein levels of LPS-induced iNOS and NO, but generated greater levels of arginase I and urea production. Furthermore, TIPE2-/- mice had higher iNOS protein levels in lung and liver and higher plasma NO concentrations, but lower levels of liver arginase I compared to LPS-treated WT controls. Interestingly, significant increases in IκB degradation and phosphorylation of JNK, p38, and IκB were observed in TIPE2-deficient macrophages following LPS challenge. These results strongly suggest that TIPE2 plays an important role in shifting L-arginase metabolism from production of NO to urea, during host inflammatory response.
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Ji'nan, P.R. China.
authors.forename: Yunwei
authors.initials: Y
authors.lastname: Lou
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Ji'nan, P.R. China.
authors.forename: Guizhong
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Ji'nan, P.R. China.
authors.forename: Minghong
authors.initials: M
authors.lastname: Geng
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Ji'nan, P.R. China.
authors.forename: Wenqian
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Ji'nan, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Cui
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Ji'nan, P.R. China.
authors.forename: Suxia
authors.initials: S
authors.lastname: Liu
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism*; D001120:Arginine / Q000378:metabolism*; D002460:Cell Line; D007249:Inflammation / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014508:Urea / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; C529002:TIPE2 protein, mouse; D014508:Urea; D001120:Arginine; D019001:Nitric Oxide Synthase; D001119:Arginase