The roles of notch signaling pathway in regulating macrophage functions

Abstract

Notch receptors are evolutionarily conserved transmembrane proteins found in metazoans. Notch receptors are expressed in both hematopoietic and immune cells including macrophages. Notch signaling is involved in regulation of proliferation, differentiation and apoptosis. Macrophages are white blood cells playing important roles in both innate and acquired immunity. Macrophages destroy antigen by phagocytosis, and mediate immune responses by cytokine secretion and antigen presentation. Activated macrophages are divided into 3 types, Ca-[Macrophage], AA-[Macrophage] and [Macrophage]-II, based on stimuli and phenotypic responses. The purposes of this study are to investigate the roles of Notch signaling in regulating macrophage functions and the relationship between expression profiles of Notch1 in three different types of activated macrophages. Expression of Notch receptors and Notch target gene, Hes1 in activated macrophages were observed and both Notch1 and Hes1 were upregulated in Ca-[Macrophage]. In addition, Ca-[Macrophage] was differentially expressed IL-12p40, iNOS, Arg1, IL-10, TNF[alpha] and MHC class II. Notch1 overexpression or inhibition of Notch signaling using [gamma]-secretase inhibitor altered expression of IL-12p40, iNOS, Arg1, IL-10, TNF[alpha], MHC class II and nitric oxide and TNF[alpha] production but did not affect the ability of macrophages to kill both Gram positive and negative bacteria. Thus, Notch1 may involve in the responses of macrophages followed this stimulation. Furthermore, Ca-[Macrophage] showed the highest Notch1 expression among three different types of macrophages. This result suggests that Notch1 may function specifically in regulating Ca-[Macrophage] function. Therefore, Notch signaling may be a novel target for intervention with macrophage activity such as in chronic inflammatory condition arising from hyperactivation of macrophages.