Separate roles of IL‐6 and oncostatin M in mouse macrophage polarization in vitro and in vivo

Abstract

Arginase-1 (Arg-1)-expressing M2-like macrophages are associated with Th2-skewed immune responses, allergic airway pathology, ectopic B16 melanoma cancer growth in murine models, and can be induced by Oncostatin M (OSM) transient overexpression in vivo. Here, we compare OSM to the gp130-cytokine IL-6 in mediating macrophage polarization, and find that IL-6 overexpression alone (Ad vector, AdIL-6) did not induce Arg-1 protein in mouse lungs at day 7, nor ectopic melanoma tumor growth at day 14, in contrast to overexpression of OSM (AdOSM). AdOSM elevated levels of IL-4, IL-5 and IL-13 in bronchoalveolar lavage fluid, whereas AdIL-6 did not. Bone marrow-derived macrophages respond with Arg-1 enzymatic activity to M2 stimuli (IL-4/IL-13), which was further elevated in combination with IL-6 stimulation; however, OSM or LIF had no detectable activity in vitro. Arg-1 mRNA expression induced by AdOSM was attenuated in IL-6-/- and STAT6-/- mice, suggesting requirements for both IL-6 and IL-4/IL-13 signaling in vivo. Ectopic B16 tumor burden was also reduced in IL-6-/- mice. Thus, OSM induces Arg-1+ macrophage accumulation indirectly through elevation of Th2 cytokines and IL-6 in vivo, whereas IL-6 acts directly on macrophages but requires a Th2 microenvironment, demonstrating distinct roles for OSM and IL-6 in M2 macrophage polarization.

IL‐6 mediates ER expansion during hyperpolarization of alternatively activated macrophages

“…We have also demonstrated that IL‐6 directly regulates macrophage pro‐fibrotic phenotype when combined with IL‐4/IL‐13 and substantiates lung fibrosis in the animal model . More recently, we also showed that of the gp130 cytokines IL‐6, oncostatin M, and leukemia inhibitory factor, IL‐6 was the only cytokine to directly mediate M2 macrophage programming in vitro and was associated with M2 macrophage accumulation in ectopic melanoma tumor growth in vivo . As these macrophages were hyperpolarized with the addition of IL‐6, it provided a unique way to study mechanisms and organelles involved in the polarization process.…”

“…2 More recently, we also showed that of the gp130 cytokines IL-6, oncostatin M, and leukemia inhibitory factor, IL-6 was the only cytokine to directly mediate M2 macrophage programming in vitro and was associated with M2 macrophage accumulation in ectopic melanoma tumor growth in vivo. 3 As these macrophages were hyperpolarized with the addition of IL-6, it provided a unique way to study mechanisms and organelles involved in the polarization process. Interestingly, the IRE1/XBP1 arm of the unfolded protein response (UPR) is thought to play a role in the differentiation of various cell types, and this is believed to include monocyte to macrophage transition, 4 eosinophil maturation, 5 dendritic cell survival 6 and B-cell to plasma cell differentiation.…”

The M2 triangle: gp130 binding cytokines drive macrophages to promote tumor growth

“…have previously been shown in isolation, their work highlights the detrimental cross‐talk between OSM, IL‐6 and M2 activation in the context of tumor metastases and tissue invasion. Although IL‐6 is often regarded as pro‐inflammatory cytokine, data emerging over the last twenty years, including the present work, challenge this simplified scenario and underline the context‐dependent nature of IL‐6 contribution to pathology . IL‐6 appears to augment the activation phenotype of macrophages imparted by other environmental cues .…”

“…On the other hand, macrophages have been shown to promote tumor growth and facilitate metastases . In this issue of Immunology & Cell Biology Dubey et al . report a collaborative network of glycoprotein 130 (gp130) binding cytokines and STAT‐6‐mediated activation that drives macrophages to promote tumor growth.…”

“…OSM induces expression of IL‐4/13, potentially through recruiting eosinophils and other IL‐4 or IL‐13 producing cells. Simultaneously, OSM induces expression of IL‐6 which promotes the upregulation of the IL‐4Rα on the cell surface of macrophages . Combined with the enhanced IL‐4/13 expression this leads to preferential M2 activation of lung macrophages as indicated by enhanced Arg1 expression (see schematic depiction in Figure ).…”