Murine MSP-STK Signaling
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Murine MSP-STK Signaling

Immune and inflammatory responses are rightly regulated to maintain a homoeostatic balance between an effective immune response and tissue damage to the host. Nitric Oxide is the principal mediator of many of the cytokine-inducible macrophage activities during a normal cell-mediated immune response. STK (Stem Cell-Derived Tyrosine Kinase), the murine homolog of the human RON (RON Protein Tyrosine Kinase/ Receptor d’origine nantais), is expressed on murine resident peritoneal macrophages. The ligand for STK, MSP (Macrophage Stimulating Protein), is a serum protein that is activated by members of the Coagulation Cascade (Tissue Clotting Factors) in response to tissue damage. MSP has an inhibitory effect on the production of Nitric Oxide by activated peritoneal macrophages. STK receptor suppresses Nitric Oxide production, therefore ameliorating the potentially tissue-damaging effects of a cell-mediated immune response, through negative regulation of the Ifn-Gamma (Interferon-Gamma) signaling pathway (Ref.1). MSP exists in blood as inactive ProMSP and upon proteolytic cleavage it is converted as active MSP. STK protein is up-regulated in burn wound epidermis and accessory structures, in proliferating cells or differentiated cells, or both and also occurs in capillaries. Tissue injury thus leads to ProMSP cleavage and activation, and macrophages that respond to MSP are key cells in tissue injury response, supporting a role for MSP and STK in the response to tissue injury (Ref.2). MSP inhibits Nitric Oxide production induced by the Gram-positive bacteria and Ifn-Gamma in peritoneal macrophages. Peritoneal macrophages also produce Superoxide which leads to liver cell injury. Such a phenomenon of mouse liver cell damage by Nitric Oxide or Superoxide is known as “Peroxynitrite-Induced Liver Damage”. The interaction of MSP and macrophages at sites of inflammation such as infection also depends on chemotactic factors such as SCyA2 (Small Inducible Cytokine-A2) and inflammatory cytokines such as IL-1Beta (Interleukin-1-Beta) and TNF-Alpha (Tumor Necrosis Factor-Alpha) that attract and activate immune cells in the affected tissue. SCyA2 plays a role in the recruitment of monocytes to sites of injury and infection. Infections of Gram-positive cocci induce mast cells to initiate TNF-Alpha production which in turn activates SCyA2. SCyA2 further interact with granulocyte progenitor cells to induce monocyte cell proliferation. The receptor for SCyA2 on monocytes is CCR2 (Chemokine CC-Motif Receptor-2) (Ref.3).

Monocytes release cytokines like M-CSF (Macrophage Colony Stimulating Factors) which helps in macrophage proliferation. MSP promotes the phagocytosis by such resident peritoneal macrophages. MSP binds to the Beta-Chain of STK receptor leading to production of cytokines like IL-12 and IL-18. These cytokines activate the NK (Natural Killer) cells and T-cells. In general, MSP inhibits the expression of iNOS (Inducible NO Synthase) leading to the seizure of Nitric Oxide and Superoxide production. Thus liver damage is prevented (Ref.4 & 5). Stimulation of murine peritoneal macrophages with MSP results in the STK-dependent up-regulation of Arginase, an enzyme associated with alternative activation that competes with iNOS for the substrate L-Arginine, the products of which are involved in cell proliferation and matrix synthesis. Ifn-Gamma and LPS (Lipopolysaccharide) blocks the ability of MSP to induce Arginase activity. Thus MSP results in the up-regulation of Arginase and inhibits their ability to produce Nitric Oxide in response to Ifn-Gamma and LPS, even in the presence of excess substrate; this shows that the inhibition of Nitric Oxide by MSP occurs primarily through its ability to regulate iNOS expression (Ref.6). The biological effects of MSP are mediated through the STK receptor tyrosine kinase, which comprises of a Alpha-chain and a transmembrane Beta-chain. The STK receptor also acts as the FV2 (Friend Virus Susceptibility-2) locus in mice. However future studies are required to delineate the mechanism by which STK regulates the host response to infection and in defining the role of this tyrosine kinase receptor in later developmental events, wound repair, inflammation, and disease processes (Ref.7 & 8).