| The link between inflammation and cancer has been known since Virchow first described leukocytes near human tumors. Recently, the power of inflammatory cells as promoting factors in tumor development has been more thoroughly explored. I examined the activation state of tumor associated macrophages (TAMS) during chemically induced pulmonary carcinogenesis. Alternative/M2 macrophage activation characterized by high arginase I, and classical/MI activation (high inducible nitric oxide synthase (iNOS)) were determined in several cancer models. The activation phenotype of bone marrow derived monocytes (BDMCs) infiltrating tumor-bearing organs mirrors that of TAMs and begins after local activation. While activation varies depending on genetic background, mode of tumor induction, and stage of progression, M2 activation predominates when tumors are present. The number of resident macrophages and degree of BDMC infiltration into lungs depends upon strain and is not influenced by activation state, indicating separate mechanisms for infiltration and activation.;Macrophages not only influence tumor development, but can influence cytokine and prostaglandin (PG) production from neighboring cells. Co-culture of an alveolar macrophage cell line (MH-S) decreased both PGE2 and PGI 2 production from primary bronchiolar Clara cells from naive and tumor-bearing mice, as well as altering inflammatory cytokines IL-6, IL-12, and IL-10.;Alternative activation of macrophages is not only associated with tumors. Inflammation induced by butylated hydroxytoluene (BHT) or Mycobacterium tuberculosis initially activates pulmonary macrophages to M1 and then to M2 during chronic inflammation. While tumors and BHT influence bone marrow macrophage populations, BDMCs are not altered upon infection with M. tuberculosis.;Macrophage activation is due to exposure to specific cytokines. IFN-gamma induces M1 activation, while IL-4 and IL-13 induce M2 activation. Macrophages and BMDCs from IFN-gamma KO mice do not become classically activated, allowing tumors to grow 1.3-fold larger than wild type mice. Genetic ablation of IL-4Ralpha, the receptor for both IL-4 and IL-13, prevents alternative activation of TAMs and BDMCs and reduces tumor size 1.3-fold compared to wild type mice. Defining the dynamic tumor-macrophage dialogue during chronic inflammation may lead to novel diagnostic and therapeutic strategies. |
