Acyltransferases

Thus, either overexpression of HO-1 in innate cells or exposure to CO prospects to inhibition of pro-inflammatory cytokines and enhancement of IL-10

Thus, either overexpression of HO-1 in innate cells or exposure to CO prospects to inhibition of pro-inflammatory cytokines and enhancement of IL-10. confers protection in experimental autoimmune encephalomyelitis (EAE) model. However, these effects were not associated with an induction of HO-1 either in innate cells such as monocytes, dendritic cells and macrophages or in the kidneys and liver of IVIG-treated EAE mice. Also, inhibition of endogenous HO-1 did not modify anti-inflammatory effects of IVIG. These results thus indicate that IVIG exerts anti-inflammatory effects impartial of HO-1 pathway. In the beginning used as replacement therapy in immune deficiencies, IVIG is also widely used for the treatment of a number of autoimmune and systemic inflammatory diseases1,2,3,4,5. Despite its therapeutic use for more than three decades, the precise mechanism by which IVIG exerts its beneficial effect is not fully comprehended. Exploration of mechanisms of IVIG Cinchonine (LA40221) is useful to define the dosage, to identify an appropriate windows and duration of treatment, and to delineate biomarkers of therapeutic response. IVIG interacts with numerous components of the immune system including dendritic cells (DCs), macrophages, T and B cells and modulate their functions6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21. These mechanisms Mouse monoclonal to NFKB1 of IVIG also Cinchonine (LA40221) reflect the functions of circulating IgG in the maintenance of immune homeostasis. Recent studies in various experimental models such as sepsis, cardiovascular pathologies, experimental autoimmune encephalomyelitis (EAE) and transplantation, and contamination models such as have highlighted the biological significance of heme oxygenase-1 (HO-1) enzymatic pathway and the reactive products of this pathway in regulating the inflammation and in the adaptation of the pathogens to the host microenvironment22,23,24,25,26,27,28. HO-1 catalyzes the degradation of heme, resulting in the liberation of equimolar amounts of iron, carbon monoxide (CO) and biliverdin. Biliverdin is usually subsequently converted to bilirubin by biliverdin reductase. Congenital defects in HO-1 expression in mice and human are associated with systemic inflammation29. HO-1 inhibits ovalbumin-induced airway inflammation by enhancing the biological activity of regulatory T cells (Tregs) in an IL-10-dependent manner30. Nevertheless, development, maintenance and the functions of Tregs under physiological conditions are not dependent on the activity of HO-131. CO and biliverdin have potent anti-inflammatory, anti-proliferative, anti-apoptotic, and antioxidant activities and exert their effects on many cell types, including cells of the immune system32. CO suppresses the pro-inflammatory response and promotes the anti-inflammatory programs of macrophages, DCs and monocytes33,34. Thus, either overexpression of HO-1 in innate cells or exposure to CO prospects to inhibition of pro-inflammatory cytokines and enhancement of IL-10. CO also inhibits the lipopolysaccharide (LPS)-mediated maturation of DCs35,36. Thus, in view of the common anti-inflammatory role exerted by both HO-1 and IVIG, we investigated if mechanisms of action of IVIG both and implicate HO-1 pathway. Results Anti-inflammatory effects of IVIG on human monocytes are not associated with induction of HO-1 It is known that IVIG exerts anti-inflammatory effects on innate cells such as monocytes, DCs and macrophages leading to suppression of inflammatory cytokines8,37,38,39. By analysing the production of IL-6, we first confirmed the anti-inflammatory action of IVIG. Unstimulated monocytes produced insignificant amount of IL-6. However, upon stimulation with LPS, a TLR4-agonist, monocytes produced large amounts of IL-6. Importantly, IVIG significantly reduced the production of IL-6, thus validating the anti-inflammatory effects of IVIG (Fig. 1a). The inhibition however was not dependant on the dose of IVIG. Open in a separate window Figure 1 Anti-inflammatory effects of IVIG on human Cinchonine (LA40221) monocytes are not associated with induction of HO-1.(a) IVIG suppresses LPS-induced IL-6 production in human monocytes. Human peripheral blood monocytes were cultured in RPMI-1640 medium with 10% fetal calf serum either alone (cells alone) or with IVIG (5 and 10?mg/ml) for 24?hours. In some conditions, after 24?hours of culture, monocytes were exposed to LPS for additional 24?hours. IL-6 in the culture supernatants was measured by ELISA (n?=?4). *p?