Response gene to complement 32 (RGC-32) expression on M2-polarized and tumor-associated macrophages is M-CSF-dependent and enhanced by tumor-derived IL-4

Abstract

Response gene to complement 32 (RGC-32) is a cell cycle regulator involved in the proliferation, differentiation and migration of cells and has also been implicated in angiogenesis. Here we show that RGC-32 expression in macrophages is induced by IL-4 and reduced by LPS, indicating a link between RGC-32 expression and M2 polarization. We demonstrated that the increased expression of RGC-32 is characteristic of alternatively activated macrophages, in which this protein suppresses the production of pro-inflammatory cytokine IL-6 and promotes the production of the anti-inflammatory mediator TGF-b. Consistent with in vitro data, tumor-associated macrophages (TAMs) express high levels of RGC-32, and this expression is induced by tumor-derived ascitic fluid in an M-CSF-and/or IL-4-dependent manner. Collectively, these results establish RGC-32 as a marker for M2 macrophage polarization and indicate that this protein is a potential target for cancer immunotherapy, targeting tumor-associated macrophages.

RGC-32 regulates reactive astrocytosis and extracellular matrix deposition in experimental autoimmune encephalomyelitis

“…In addition, we have demonstrated for the first time that RGC-32 can influence the astrocytic phenotype in vivo during EAE, suggesting that RGC-32 plays an important role in the differentiation of astrocytes in an inflammatory milieu. These data, in conjunction with previous reports of a role for RGC-32 in the differentiation of Th17 cells [7] and monocytes [35], suggest a broader role for this protein in cellular differentiation during inflammatory conditions.…”

Altering macrophage polarization in the tumor environment: the role of response gene to complement 32

“…Zhao et al 6 further showed that ascites tumor fluid enhanced RGC-32 and M2-type cytokines, in accordance with the evidence that either tumors or tumorassociated cells can produce factors that decrease the M1/M2 ratio and inhibit effective antitumor activity.…”

“…2 Thus, decreasing the proportion of M2-type and/or increasing the proportion of M1-type macrophages in tumors could be a very promising strategy to inhibit tumor growth and metastases. 325 In a study reported in this issue, Zhao et al 6 evaluated the expression and role of response gene to complement 32 (RGC-32) in macrophages and tumorassociated macrophages (TAMs). First, they demonstrated that both a cultured macrophage-like cell line and monocyte-derived macrophages up-regulated RGC-32 when exposed to either IL-4 or macrophage colony-stimulating factor.…”

“…Thus, the study by Zhao et al 6 shows that inhibiting TGF-b by targeting RGC-32 is a promising approach to altering the predominant phenotype of TAMs from M2 to M1. It will be interesting to see whether future studies show that inhibition of RGC-32 activity in vivo can slow cancer growth or otherwise modulate macrophage activity under circumstances in which M1-or M2-type responses are desirable.…”

Decreased expression of response gene to complement 32 in psoriasis and its association with reduced M2 macrophage polarization

“…The M1/M2 macrophage polarization scheme parallels the T‐helper (Th)1/Th2 paradigm, whereby the M1 phenotype produces pro‐inflammatory cytokines and the M2 phenotype is more of an anti‐inflammatory nature . RGC‐32 mRNA expression was significantly higher in M2 than in M1 macrophages . Pro‐inflammatory activities of macrophages is crucial in psoriasis.…”