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The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailed molecular mechanisms underlying the relationship between these two cell types remain unclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger protein that is essential for early mammalian development, plays critical roles in GSC maintenance and M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL, encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicity of GSCs through production of prostaglandin E 2 (PGE 2 ), which stimulates β-catenin activation of GSC and M2-like TAM polarization. We identify M2-like signature downregulated by which MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mouse xenograft model by blocking PGE 2 production. Taken together, our results suggest that blocking the interplay between GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially novel therapeutic option for GBM patients.

Purpose: Aberrant regulation of innate immune cells such as macrophages has been implicated in the onset and progression of type 1 diabetes (T1D). Macrophages from nonobese diabetic (NOD) mouse, an animal model of T1D, entail developmental and functional defects that are often associated with hypo-responsiveness to interferon (IFN)-γ. We aimed to uncover a mechanism underlying this phenomenon., Methods: We analyzed the receptor pathway along with the response of macrophages exposed to IFN-γ and the related IFNs such as IFN-α/β., Results: We found that NOD macrophages failed to fully respond to IFN-γ but not to IFN-α for the production of inflammatory cytokines (e.g. TNF-α and IL-12). NOD macrophages were also resistant to apoptotic pathway induced by IFN-γ and LPS. Analyses of receptor pathway revealed that STAT1 pathway of intracellular signaling was selectively impaired in NOD macrophages exposed to IFN-γ but not to IFN-α/β. Further, these defects correlated with a low phosphorylation level of JAK2, and were related to impaired up-regulation of surface IFN-γ receptor 2 (IFN-γR2) by IFN-γ., Conclusion: Taken together, our results suggest that NOD macrophages have a selective defect in IFN-γ but not IFN-α/β receptor pathway. As IFN-γ and IFN-α have been implicated in the development of autoimmunity towards β-cells, such an unanticipated selectivity in IFN responsiveness may provide a new insight into the pathogenesis of T1D.

Abstract: Korean mistletoe lectin (KML-C) is an adjuvant that activates systemic and mucosal immune cells to release cytokines including TNF-α, which induces immunity against viruses and cancer cells. Although the immunomodulatory activity of KML-C has been well established, the underlying mechanism of action of KML-C has yet to be explored. When mouse peritoneal macrophages were treated with KML-C, both transcription and translation of TLR4 were upregulated. KML-C-induced TLR4 downstream events were similar to those activated by LPS: the upregulation of interleukin-1 receptor-associated kinase-1 (IRAK1); resulting in macrophage activation and TNF-α production. When TLR4 was blocked using a TLR4-specific neutralizing antibody, TNF-α production from the macrophages was significantly inhibited. Moreover, TLR4-deficient mouse macrophages treated with KML-C also secreted greatly reduced level of TNF-α secretion. Finally, TLR4 molecules were co-precipitated with KML-C, to which agarose beads were conjugated, indicating that those molecules are associated. These data indicate that KML-C activates mouse macrophages to secrete TNF-α by interacting with the TLR4 molecule and activating its signaling pathways. [Copyright &y& Elsevier]