The modulation of macrophage activation by tyrosine phosphorylation.

Activated macrophages are a critical component of our antimicrobial armamentarium. Unfortunately, the lipid mediators and free radicals that these cells produce are not only toxic to potential pathogens, but also to the host. Thus the modulation of these activities can mitigate an overzealous immune response and thereby prevent host cell injury. Two families of receptor tyrosine kinases (RTK) in macrophages, the RON/STK and the Tyro3 families of protein kinases, will be examined in this review with an emphasis on their roles in modulating the effector functions of activated macrophages. Both families of receptors are capable of down-regulating the inflammatory response of macrophages to lipopolysaccharide, and both families of RTK's are structurally related. An analysis of the intracellular domains of RON/STK and Tyro3 reveal a common multi-substrate binding site, which can recruit common signaling molecules such as growth factor receptor bound 2 (Grb2) and phosphatidylinositol 3-kinase (PI3-K). The observations relating to a modulation of macrophage effector mechanisms by these receptors open unexplored avenues for the development of pharmacological immunomodulators with the potential to exploit elements of this common pathway.