Augmented lipopolysaccharide-induced TNF-alpha production by peritoneal macrophages in type 2 diabetic mice is dependent on elevated glucose and requires p38 MAPK

• Published in: Journal of Immunology 2007-01, Vol.178 (2), p.663-670
• Main Authors: Sherry, Christina L, O'Connor, Jason C, Kramer, Jason M, Freund, Gregory G
• Format: Article
• Language: English
• Subjects: Animals; Diabetes Mellitus, Type 2 - metabolism; Enzyme Activation - drug effects; Glucose - metabolism; Lipopolysaccharides - pharmacology; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - metabolism; Mice; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation - drug effects; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.178.2.663

Dysregulated inflammation is a complication of type 2 diabetes (T2D). In this study, we show that augmented LPS-induced TNF-alpha production by resident peritoneal macrophages (PerMphi) in type 2 diabetic (db/db) mice is dependent on elevated glucose and requires p38 MAPK. Intraperitoneal LPS administered to db/db and nondiabetic (db/+) mice induced 3- and 4-fold more TNF-alpha in the peritoneum and serum, respectively, of db/db mice as compared with db/+ mice. Examination of the TLR-4/MD2 complex and CD14 expression showed no difference between db/db and db/+ PerMphi. Ex vivo stimulation of PerMphi with LPS produced a similar 3-fold increase in TNF-alpha production in db/db PerMphi when compared with db/+ PerMphi. PerMphi isolated from db/+ mice incubated in high glucose (4 g/L) medium for 12 h produced nearly 2-fold more TNF-alpha in response to LPS than PerMphi incubated in normal glucose medium (1 g/L). LPS-dependent stimulation of PI3K activity, ERK1/2 activation, and p38 kinase activity was greater in PerMphi from db/db mice as compared with db/+ mice. Only inhibition of p38 kinase blocked LPS-induced TNF-alpha production in PerMphi from db/db mice. Taken together, these data indicate that augmented TNF-alpha production induced by LPS in macrophages during diabetes is due to hyperglycemia and increased LPS-dependent activation of p38 kinase.