Cytokine-induced macrophage differentiation: a tale of 2 genes

Macrophages are versatile cells found in every tissue in the body. They mus t perform a number of diverse cellular functions that allow them to kill in vading microorganisms and neoplastic cells as well as produce growth factor s involved in wound healing. Macrophages that develop these diverse functio ns arise from a common precursor. By a process of selective adaptation, the common precursor monocyte/macrophage differentiates into a distinctive mac rophage with a different and specific phenotype, characterized by the expre ssion of a specific set of gene products. The local environment plays a cri tical role in shaping or directing the pattern or pathway of macrophage dif ferentiation. The authors have focused on 2 specific macrophage differentia tion pathways in a murine bone marrow-derived macrophage model. One pathway is believed to play a role in wound repair and is characterized by the ind uction of insulin-like growth factor-1 (IGF-I). The second pathway is invol ved in macrophage cytocidal activation and is characterized by the inductio n of the inducible form of nitric oxide synthase (iNOS). The pleotropic cyt okine tumour necrosis factor-alpha (TNF-alpha) appears to mediate macrophag e differentiation along both of these pathways. Interferon-gamma (IFN-gamma ) however, appears to act as a molecular switch. in the presence of IFN-gam ma, stimulation of macrophages with TNF-alpha results in macrophage differe ntiation along a pathway in which iNOS is expressed, whereas, in the absenc e of IFN-II, stimulation of macrophages with TNF-alpha results in different iation along a pathway in which IGF-I is expressed. The authors focus on so me of the molecular events involved in TNF-alpha and IFN-gamma signal trans duction and the regulation of iNOS and IGF-I genes in macrophages.