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

Christina L. Sherry, Jason C. O'Connor, Jason M. Kramer, Gregory G. Freund

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Dysregulated inflammation is a complication of type 2 diabetes (T2D). In this study, we show that augmented LPS-induced TNF-α production by resident peritoneal macrophages (PerMφ) 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-α 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/+ PerMφ. Ex vivo stimulation of PerMφ with LPS produced a similar 3-fold increase in TNF-α production in db/db PerMφ when compared with db/+ PerMφ. PerMφ isolated from db/+ mice incubated in high glucose (4 g/L) medium for 12 h produced nearly 2-fold more TNF-α in response to LPS than PerMφ incubated in normal glucose medium (1 g/L). LPS-dependent stimulation of PI3K activity, ERK1/2 activation, and p38 kinase activity was greater in PerMφ from db/db mice as compared with db/+ mice. Only inhibition of p38 kinase blocked LPS-induced TNF-α production in PerMφ from db/db mice. Taken together, these data indicate that augmented TNF-α production induced by LPS in macrophages during diabetes is due to hyperglycemia and increased LPS-dependent activation of p38 kinase.

Original languageEnglish (US)
Pages (from-to)663-670
Number of pages8
JournalJournal of Immunology
Volume178
Issue number2
DOIs
StatePublished - Jan 15 2007
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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