title: Potent suppression of arginase 1 expression in murine macrophages by low dose endotoxin.
abstract: Macrophages can respond to diverse signals and adopt multiple phenotypes. Although interleukin-4 (IL-4) is shown to potently induce the expression of arginase 1 and contribute to differentiation of macrophages to the anti-inflammatory M2 phenotype, other modulators may potentiate or reduce the effect of IL-4. In this report, we focus on the combinatorial effects of IL-4 with all-trans retinoic acid (ATRA) and lipopolysaccharide (LPS). ATRA has been shown to contribute to the resolution of inflammation, however it has not been linked to arginase 1 expression in macrophages. We demonstrate that although ATRA alone has no effect on the expression or activities of arginase 1, ATRA can dramatically potentiate the induction of arginase 1 by IL-4. On the other hand, high doses of LPS, such as those seen in septic shock, can induce the expression of both M1 and M2 mediators in macrophages. The effects of subclinical doses of LPS, which are prevalent in humans with adverse health conditions, on macrophage differentiation are not well studied. We demonstrate that low dose LPS can effectively suppress the expression of arginase 1 induced by IL-4 and ATRA. Mechanistically, we report that the interleukin-1 receptor-associated kinase 1 (IRAK-1) and Toll-interacting-protein (Tollip) are involved in the suppressive effect of low dose LPS. Our study reveals dynamic modulation of arginase 1 expression in macrophages by competing agonists, and bears relevance for potential intervention of chronic diseases.
authors.affiliation: Department of Biological Sciences, Virginia Tech Blacksburg, VA 24061-0910.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Surace
authors.forename: Liwu
authors.initials: L
authors.lastname: Li
keywords: Low grade inflammation; arginase expression; macrophages; molecular mechanisms