Intravenous immunoglobulin skews macrophages to an anti-inflammatory, IL-10-producing activation state

Journal of Leukocyte Biology

Zheng Yu Zhao¹  Naomi Hotte¹  Laura M. Sly¹  Mario Fidanza¹  Judith Hellman¹  Karen L. Madsen and¹  Lisa K. Kozicky¹  Gregor S. D. Reid¹  Kevin Wilhelmsen¹  Susan C. Menzies¹ 

[1] Division of Gastroenterology and  Division of Oncology, Hematology, and Blood and Marrow Transplantation, Department of Pediatrics, Michael Cuccione Childhood Cancer Research Program, Child & Family Research Institute, British Columbia Children™s Hospital, and the University of British Columbia, Vancouver, British Columbia, Canada; Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, California, USA; and Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada

关键词: macrophage activation;    regulatory macrophages;    Fc receptors;    map kinases;    sepsis;   

DOI  :  10.1189/jlb.3VMA0315-078R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Intravenous Ig is used to treat autoimmune or autoinflammatory disorders, but the mechanism by which it exerts its immunosuppressive activity is not understood completely. To examine the impact of intravenous Ig on macrophages, we compared cytokine production by LPS-activated macrophages in the presence and absence of intravenous Ig. Intravenous Ig treatment induced robust production of IL-10 in response to LPS, relative to LPS stimulation alone, and reduced production of proinflammatory cytokines. This anti-inflammatory, intravenous Ig-induced activation was sustained for 24 h but could only be induced if intravenous Ig were provided within 1 h of LPS stimulation. Intravenous Ig activation led to enhanced and prolonged activation of MAPKs, Erk1/2, p38, and Erk5, and inhibition of each reduced intravenous Ig-induced IL-10 production and suppression of IL-12/23p40. IL-10 production occurred rapidly in response to intravenous Ig + LPS and was sufficient to reduce proinflammatory IL-12/23p40 production in response to LPS. IL-10 induction and reduced IL-12/23p40 production were transcriptionally regulated. IL-10 played a direct role in reducing proinflammatory cytokine production by macrophages treated with intravenous Ig + LPS, as macrophages from mice deficient in the IL-10R β chain or in IL-10 were compromised in their ability to reduce proinflammatory cytokine production. Finally, intraperitoneal injection of intravenous Ig or intravenous Ig + LPS into mice activated macrophages to produce high levels of IL-10 during subsequent or concurrent LPS challenge, respectively. These findings identify IL-10 as a key anti-inflammatory mediator produced by intravenous Ig-treated macrophages and provide insight into a novel mechanism by which intravenous Ig may dampen down inflammatory responses in patients with autoimmune or autoinflammatory diseases.

【 授权许可】

Unknown