Search

A major risk factor for colon cancer growth and progression is chronic inflammation. We have shown that the MAPK-activated protein kinase 2 (MK2) pathway is critical for colon tumor growth in colitis-associated and spontaneous colon cancer models. This pathway is known to regulate expression of the tumor-promoting cytokines, IL-1, IL-6, and TNF-α. However, little is known about the ability of MK2 to regulate chemokine production. This is the first study to demonstrate this pathway also regulates the chemokines, MCP-1, Mip-1α, and Mip-2α (MMM). We show that these chemokines induce tumor cell growth and invasion in vitro and that MK2 inhibition suppresses tumor cell production of chemokines and reverses the resulting pro-tumorigenic effects. Addition of MMM to colon tumors in vivo significantly enhances tumor growth in control tumors and restores tumor growth in the presence of MK2 inhibition. We also demonstrate that MK2 signaling is critical for chemokine expression and macrophage influx to the colon tumor microenvironment. MK2 signaling in macrophages was essential for inflammatory cytokine/chemokine production, whereas MK2−/− macrophages or MK2 inhibition suppressed cytokine expression. We show that addition of bone marrow-derived macrophages to the tumor microenvironment enhances tumor growth in control tumors and restores tumor growth in tumors treated with MK2 inhibitors, while addition of MK2−/− macrophages had no effect. This is the first study to demonstrate the critical role of the MK2 pathway in chemokine production, macrophage influx, macrophage function, and tumor growth.

Background and AimsThe role of programmed cell death protein 1 (PD-1) and its ligands in the dysregulation of T helper immune responses observed in the inflammatory bowel disease (IBD) is unclear. Recently, a novel concept emerged that CD90+ colonic (myo)fibroblasts (CMFs), also known as stromal cells, act as immunosuppressors, and are among the key regulators of acute and chronic inflammation. The objective of this study was to determine if the level of the PD-1 ligands is changed in the IBD inflamed colonic mucosa and to test the hypothesis that changes in IBD-CMF-mediated PD-1 ligand-linked immunosuppression is a mechanism promoting the dysregulation of Th1 cell responses.MethodsTissues and cells derived from Crohn’s disease (CD), ulcerative colitis (UC), and healthy individuals (N) were studied in situ, ex vivo, and in culture.ResultsA significant increase in programmed death-ligand 1 (PD-L1) was observed in the inflamed UC colonic mucosa when compared to the non-inflamed matched tissue samples, CD, and healthy controls. UC-CMFs were among the major populations in the colonic mucosa contributing to the enhanced PD-L1 expression. In contrast, PD-L1 expression was decreased in CD-CMFs. When compared to CD-CMFs and N-CMFs, UC-CMFs demonstrated stronger suppression of IL-2, Th1 transcriptional factor Tbet, and IFN-γ expression by CD3/CD28-activated CD4+ T cells, and this process was PD-L1 dependent. Similar observations were made when differentiated Th1 cells were cocultured with UC-CMFs. In contrast, CD-CMFs showed reduced capacity to suppress Th1 cell activity and addition of recombinant PD-L1 Fc to CD-CMF:T cell cocultures partially restored the suppression of the Th1 type responses.ConclusionWe present evidence showing that increased PD-L1 expression suppresses Th1 cell activity in UC. In contrast, loss of PD-L1 expression observed in CD contributes to the persistence of the Th1 inflammatory milieu in CD. Our data suggest that dysregulation of the Th1 responses in the inflamed colonic mucosa of IBD patients is promoted by the alterations in PD-L1 expression in the mucosal mesenchymal stromal cell compartment.