Mechanisms and intervention strategies for chronic low-grade inflammation. (P1361)

• Published in: The Journal of immunology (1950) Vol. 190; no. 1_Supplement; pp. 63 - 63.33
• Main Authors: Morris, Matt, Li, Liwu
• Format: Journal Article
• Language: English
• Published: 01-05-2013
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.190.Supp.63.33

Low-grade inflammation contributes to diseases such as atherosclerosis, arthritis, and diabetes. Contributors to low-grade inflammation include circulating microbial products such as lipopolysaccharide (LPS). High plasma levels of LPS cause acute shock, but low levels of LPS predispose individuals to mild inflammatory conditions. This predisposition results from mild expression of pro-inflammatory cytokines without compensating anti-inflammatory modulators, leading to persistent, unresolved inflammation. Despite the clinical importance of chronic inflammation, its underlying mechanisms are poorly understood. Glycogen synthase kinase 3 (GSK3) is implicated in the pro-inflammatory conditioning of innate immunity. We tested whether inhibition of GSK3 and upstream kinases can prevent inflammatory skewing by low dose LPS. We measured the expression of pro-inflammatory IL-6 and anti-inflammatory IL-33 in pre-monocytic THP-1 cells treated with low dose LPS (50 pg/mL) and a GSK3 inhibitor. We observed that while low dose LPS alone induced mild expression of IL-6, GSK3 inhibition skews THP-1 cells into an anti-inflammatory state by augmenting the induction of IL-33 by low dose LPS while diminishing the induction of IL-6. We found that broad inhibition of tyrosine kinases also diminishes IL-6 induction. These observations suggest a complex intracellular circuit that dynamically modulates the expression of pro- and anti-inflammatory mediators upon treatment with low dose LPS.