IL-6–producing M2 macrophages linked to intestinal tumors in UC
MedWire News: IL-6-producing F4/80+CD11bhighGr1low M2 macrophages may be involved in the generation of intestinal tumors in patients with longstanding ulcerative colitis (UC), suggest study findings.
Patients with prolonged UC frequently develop colorectal adenocarcinoma for reasons that are not fully understood, although evidence from murine models suggests that the presence of chronic inflammation provides an environment favoring the growth of neoplastic cells.
To investigate inflammation-associated colonic tumorigenesis, Stefan Fichtner-Feigl (University of Regensburg, Germany) and co-authors developed a chronic form of oxazolone-induced colitis in mice, which bears resemblance to UC due to the presence of interleukin (IL)-13-producing natural killer T (NKT) cells.
When the team induced tumors using azoxymethane, this was accompanied by the co-appearance of F4/80+CD11bhighGr1low M2 macrophages that underwent activation as a result of exposure to IL-13 produced by NKT cells. Furthermore, these cells were found to be a major source of tumor-supporting factors including IL-6 and epidermal-growth factor.
Tumor development was found to be dependent on the presence of inflammation, since reversal of inflammation by IL-13 blockade or NKT cell depletion resulted in an almost tumor-free colon. Fitchner-Feigl and team say it is possible that IL-13-producing NKT cells generated during oxa-colitis act on macrophages drawn into sites of tumor development to induce their differentiation into tumor-supporting cells.
"These findings thus establish that the Th2-like inflammatory milieu of oxa-colitis is equally capable of supporting induced tumor development as the more usually studied Th1/Th17 inflammatory milieu of dextran sodium sulfate-induced colitis," say the researchers.
When the team then analyzed mice deficient in the myeloid differentiation primary response gene 88 (Myd88-/-), they found that these mice did not support tumor development despite still presenting chronic oxa-colitis. Importantly, wild-type, but not Myd88-/-, mice produced increased amounts of IL-6.
Furthermore, a correlation was found between cessation of IL-6 and transforming growth factor-β1 production by M2 and F4/80+CD11bhighGr1intermediate macrophages, respectively. Administration of IL-6 restored the ability of Myd88-/- mice to support azoxymethane-induced tumor growth, thus showing that deficient IL-6 production underlies the inability of Myd88-/- mice to facilitate tumor development.
"It will therefore be valuable to determine whether patients with UC have increased numbers of [IL-6-producing F4/80+CD11bhighGr1low] macrophages in the colonic mucosa and thus whether such macrophages can be a predictor of neoplastic development," conclude Fichtner-Feigl et al in the Journal of Clinical Investigation.
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By Ingrid Grasmo