Abstract
EGF receptor (EGFR) in tumor cells serves as a tumor promoter. However, information about EGFR activation in macrophages in regulating M2 polarization and tumor development is limited. This study aimed to investigate the effects of EGFR activation in macrophages on M2 polarization and development of gastrointestinal tumors. IL-4, a cytokine to elicit M2 polarization, stimulated release of an EGFR ligand, HB-EGF, and transactivation and down-regulation of EGFR in Raw 264.7 cells and peritoneal macrophages from WT mice. Knockdown of HB-EGF in macrophages inhibited EGFR transactivation by IL-4. IL-4-stimulated STAT6 activation, Arg1 and YM1 gene expression, and HB-EGF production were further enhanced by inhibition of EGFR activity in Raw 264.7 cells using an EGFR kinase inhibitor and in peritoneal macrophages from Egfr(wa5) mice with kinase inactive EGFR and by knockdown of EGFR in peritoneal macrophages from Egfr(fl/fl) LysM-Cre mice with myeloid cell-specific EGFR deletion. Chitin induced a higher level of M2 polarization in peritoneal macrophages in Egfr(fl/fl) LysM-Cre mice than that in Egfr(fl/fl) mice. Accordingly, IL-4-conditioned medium stimulated growth and epithelial-to-mesenchymal transition in gastric epithelial and colonic tumor cells, which were suppressed by that from Raw 264.7 cells with HB-EGF knockdown but promoted by that from Egfr(wa5) and Egfr(fl/fl) LysM-Cre peritoneal macrophages. Clinical assessment revealed that the number of macrophages with EGFR expression became less, indicating decreased inhibitory effects on M2 polarization, in late stage of human gastric cancers. Thus, IL-4-stimulated HB-EGF-dependent transactivation of EGFR in macrophages may mediate inhibitory feedback for M2 polarization and HB-EGF production, thereby inhibiting gastrointestinal tumor growth.
Highlights
20462 JOURNAL OF BIOLOGICAL CHEMISTRY vealed that the number of macrophages with EGF receptor (EGFR) expression became less, indicating decreased inhibitory effects on M2 polarization, in late stage of human gastric cancers
It is known that cytokines, such as IL-4, IL-10, IL-13, IFN-␥, TNF, macrophage colony-stimulting factor (MCSF), TGF, and PGE2 produced by lymphocytes and tumor cells promote M2 polarization and functions of Tumor-associated macrophages (TAMs) [11]
IL-4 Stimulates Transactivation of EGFR in Macrophages, Which Requires HB-EGF Release—To determine whether EGFR signaling contributes to regulation of M2 polarization, we first studied the effects of IL-4 on EGFR activation in macrophages
Summary
20462 JOURNAL OF BIOLOGICAL CHEMISTRY vealed that the number of macrophages with EGFR expression became less, indicating decreased inhibitory effects on M2 polarization, in late stage of human gastric cancers. Tumor-associated macrophages (TAMs) in the tumor microenvironment usually exhibit M2 polarization in human and mouse models of cancers [5, 6] and possess pro-tumorigenic activities in most cancers, including promoting tumor cell proliferation, migration, and invasion, increasing angiogenesis, and suppressing immunity through secretion of growth factors such as HB-EGF, EGF, CSF-1, VEGF, and PDGF, enzymes, including metalloproteinases (MMPs), and cytokines, such as IL-6, IL-10, and TNF [7]. Negative Feedback for M2 Polarization by EGFR in Macrophages there is a strong correlation between the abundance of TAMs and poor prognosis in most cancers Both positive and negative associations between TAMs and clinical outcomes have been reported in lung, gastric, prostate, and bone cancers, depending on tumor types and stages (8 –10). The mechanism underlying the diverse functions of TAMs in different tumor microenvironment remains unclear
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