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Augmented lipopolysaccharide-induced TNF-alpha production by peritoneal macrophages in type 2 diabetic mice is
Christina L Sherry1, Jason C O'Connor, Jason M Kramer
1Division of Nutritional Sciences, Integrative Immunology and Behavior Program, University of Illinois, 506 South Mathews Avenue, Urbana, IL 61801, USA.
Abstract:
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.
Insights
Type 2 diabetes (T2D) increases inflammation. High glucose in T2D elevates lipopolysaccharide (LPS)-induced TNF-alpha production in macrophages, requiring p38 MAPK activation for this inflammatory response.
Area of Science:
- Immunology
- Endocrinology
- Molecular Biology
Background:
- Dysregulated inflammation is a key complication in type 2 diabetes (T2D).
- Macrophages play a central role in inflammatory processes.
- Understanding the molecular mechanisms driving inflammation in T2D is crucial for therapeutic development.
Purpose of the Study:
- To investigate the mechanisms behind augmented lipopolysaccharide (LPS)-induced TNF-alpha production in macrophages from type 2 diabetic mice.
- To determine the role of elevated glucose and specific signaling pathways, such as p38 MAPK, in this process.
Main Methods:
- Comparison of TNF-alpha production in response to LPS between peritoneal macrophages (PerMphi) from type 2 diabetic (db/db) mice and non-diabetic (db/+) mice.
- Ex vivo stimulation of PerMphi with LPS in varying glucose concentrations.
- Analysis of signaling pathway activation (PI3K, ERK1/2, p38 MAPK) and the effect of p38 kinase inhibition.
Main Results:
- db/db mice exhibited significantly higher LPS-induced TNF-alpha production in both peritoneal fluid and serum compared to db/+ mice.
- PerMphi from db/+ mice cultured in high glucose showed increased TNF-alpha production upon LPS stimulation.
- LPS-induced p38 MAPK activation was significantly greater in PerMphi from db/db mice, and its inhibition abolished TNF-alpha production.
Conclusions:
- Augmented TNF-alpha production in macrophages during diabetes is primarily driven by hyperglycemia.
- The p38 MAPK pathway is essential for the increased inflammatory response to LPS in the context of type 2 diabetes.
- These findings highlight the link between hyperglycemia, macrophage activation, and inflammation in T2D.
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