IL-6 increases B-cell IgG production in a feed-forward proinflammatory mechanism to skew hematopoiesis and elevate myeloid production.
Src homology 2 domain-containing inositol 5-phosphatase (SHIP(-/-)) animals display an age-related increase in interleukin-6 (IL-6), a decrease in B lymphopoiesis, and an elevation in myelopoiesis. We investigated the origin of the IL-6 production and show that it is largely produced by peritoneal and splenic macrophages. IL-6 production by these macrophages is not a direct result of the loss of SHIP: IL-6 production is not spontaneous, is absent from bone marrow-derived macrophages, declines with prolonged culture of macrophages, and requires a stimulus present in vivo. The IL-6-rich peritoneal cavity of SHIP(-/-) mice shows more than 700-fold more immunoglobulin G (IgG) than wild-type, approximately 20% of which is aggregated or in an immune complex and contains B220(+) cells that secrete IgG. The SHIP-deficient peritoneal macrophages show evidence of IgG receptor stimulation. Animals lacking both the signal-transducing gamma-chain of IgG receptors and SHIP or Ig and SHIP produce less IL-6. The data indicate a feed-forward process in which peripheral macrophages, responding through IgG receptors to secreted IgG, produce IL-6, to support further B-cell production of IgG. Because of the proinflammatory phenotype of SHIP(-/-) animals, these findings emphasize the importance of IL-6-neutralizing strategies in autoimmune and proinflammatory diseases.
Maeda
Kenichiro
K
Oklahoma Medical Research Foundation, Program in Immunobiology & Cancer, Oklahoma City, OK 73104, USA.
Mehta
Harshini
H
Drevets
Douglas A
DA
Coggeshall
K Mark
KM
D000375:Aging / Q000235:genetics / Q000276:immunology; D000818:Animals; D000917:Antibody Formation / Q000235:genetics / Q000276:immunology*; D000936:Antigen-Antibody Complex / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000072181:Inositol Polyphosphate 5-Phosphatases; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D038042:Myelopoiesis / Q000235:genetics / Q000276:immunology*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D000936:Antigen-Antibody Complex; D007074:Immunoglobulin G; D015850:Interleukin-6; D017452:Receptors, IgG; D010744:Phosphoric Monoester Hydrolases; D017493:Leukocyte Common Antigens; D000072181:Inositol Polyphosphate 5-Phosphatases