UBC Theses and Dissertations
Intravenous immunoglobulin skews macrophages to an anti-inflammatory, IL-10 producing activation state Kozicky, Lisa
Macrophages initiate the immune response and contribute to the inflammation that characterizes many diseases. Macrophages play an equally important role in turning off the inflammatory response, by producing the anti-inflammatory cytokine IL-10. Intravenous immunoglobulin (IVIg) is a drug made up of pooled polyclonal IgGs, which is used to treat immune-mediated diseases. However, its mechanism of action is not completely understood. We found that IVIg induced high production of IL-10 and low production of pro-inflammatory cytokines by murine bone marrow-derived macrophages (BMDMs) treated with lipopolysaccharide (LPS), an inflammatory stimulus. MAPKs, Erk5, Erk1/2, and p38, were activated by co-stimulation with IVIg and LPS and their activation was required for IL-10 production. In vivo, murine peritoneal macrophages also produced high levels of IL-10 and low levels of IL-12/23p40 when treated with IVIg + LPS. Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the intestine. IVIg-treated macrophages or IVIg treatment ameliorated intestinal inflammation in mice during dextran sulfate sodium (DSS)-induced colitis. Moreover, IVIg-induced macrophage IL-10 production was required for IVIg-mediated protection. In human monocytes, IVIg also increased IL-10 production and reduced pro-inflammatory cytokine production in response to LPS. IVIg-induced IL-10 production required the FcγRI and FcγRIIB as well as activation of MAPKs, ERK1/2 and p38. An FcγRIIA gene variant predisposes people to develop immune-mediated diseases, such as IBD, and has been linked to a failure to respond to antibody therapy. The FcγRIIA disease risk variant changes this receptor from a low to a high affinity receptor. My results demonstrated that IVIg-induced anti-inflammatory responses were compromised in monocytes from people with the FcγRIIA risk variant. Together, these results describe a novel mechanism of action for IVIg, the induction of anti-inflammatory, IL-10 producing macrophages. IVIg may provide an effective therapeutic option to treat people with IBD. However, induction of this anti-inflammatory activation state may be impaired in monocytes from people with the disease-associated FcγRIIA gene variant. In summary, understanding IVIg’s mechanism of action may inform new applications, prompt development of new therapeutic strategies for immune-mediated diseases, and identify individuals for whom IVIg will be most effective.
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