The Role of Src Kinase in Macrophage-Mediated Inflammatory Responses

Abstract

Src kinase (Src) is a tyrosine protein kinase that regulates cellular metabolism, survival, and proliferation. Many studies have shown that Src plays multiple roles in macrophage-mediated innate immunity, such as phagocytosis, the production of inflammatory cytokines/mediators, and the induction of cellular migration, which strongly implies that Src plays a pivotal role in the functional activation of macrophages. Macrophages are involved in a variety of immune responses and in inflammatory diseases including rheumatoid arthritis, atherosclerosis, diabetes, obesity, cancer, and osteoporosis. Previous studies have suggested roles for Src in macrophage-mediated inflammatory responses; however, recently, new functions for Src have been reported, implying that Src functions in macrophage-mediated inflammatory responses that have not been described. In this paper, we discuss recent studies regarding a number of these newly defined functions of Src in macrophage-mediated inflammatory responses. Moreover, we discuss the feasibility of Src as a target for the development of new pharmaceutical drugs to treat macrophage-mediated inflammatory diseases. We provide insights into recent reports regarding new functions for Src that are related to macrophage-related inflammatory responses and the development of novel Src inhibitors with strong immunosuppressive and anti-inflammatory properties, which could be applied to various macrophage-mediated inflammatory diseases.

Oxidized Low-Density Lipoprotein Stimulates Macrophage 18F-FDG Uptake via Hypoxia-Inducible Factor-1α Activation Through Nox2-Dependent Reactive Oxygen Species Generation

“…On examining candidate kinase pathways, the metabolic effect of oxLDL was completely abrogated by an Src inhibitor (PP2), a critical player in the functional activation of macrophages (28), as well as by a PI3K inhibitor (LY-294002), consistent with the regulatory role of this pathway in glucose metabolism and immune cell activation (29).…”

The importance of Src signaling in sarcoma

“…SRC is a proto-oncogene encoding a non-receptor tyrosine kinase, similar to the v-Src gene of the Rous sarcoma virus (14), which was initially discovered by Bishop and Varmus (15). The Src protein is formed of seven functional regions: i) N-terminal Src homology domain 4 (SH4) containing a myristic acid moiety, essential for its localization to the inner surface of the cell membrane; ii) a unique domain providing functional specificity to each member of the Src family; iii) SH3 domain, which binds proline-rich sequences to mediate intra-and intermolecular interactions; iv) SH2 domain, which binds phosphorylated tyrosine residues on Src and other proteins; v) a catalytic domain (SH1); and vi) C-terminal tail containing negative-regulatory Tyr530 (in humans) (16)(17)(18) (Fig.…”

Boerhavia diffusa L. ethanol extract suppresses inflammatory responses via inhibition of Src/Syk/TRAF6

“…5) revealed that the Bd-EE extract was able to directly suppress Syk and Src, which are important protein tyrosine kinases in the NF-κB pathway (Johnson, Li, & Pearlman, 2008). According to several studies, Src and Syk play varied roles in macrophage-mediated innate immunity, including immune cell cycle, phagocytosis, the production of inflammatory cytokines/mediators, and gene expression (Byeon et al, 2012;Frommhold et al, 2007;Yi et al, 2014). Alternatively, collaboration of the Syk and TLR4/MyD88 pathways results in the sustained degradation of IκBα, enhancing NF-κB nuclear translocation, resulting in the control of infectious materials ( Lee et al, 2009;Yi et al, 2014).…”