gC1q receptor ligation selectively down-regulates human IL-12 production through activation of the phosphoinositide 3-kinase pathway.
gC1qR, a complement receptor for C1q, plays a pivotal role in the regulation of inflammatory and antiviral T cell responses. Several pathogens, including hepatitis C virus, exploit gC1qR-dependent regulatory pathways to manipulate host immunity. However, the molecular mechanism(s) of gC1qR signaling involved in regulating inflammatory responses remains unknown. We report the selective inhibition of TLR4-induced IL-12 production after cross-linking of gC1qR on the surface of macrophages and dendritic cells. Suppression of IL-12 did not result from increased IL-10 or TGF-beta, but was dependent on PI3K activation. Activation of PI3K and subsequent phosphorylation of Akt define an intracellular pathway mediating gC1qR signaling and cross-talk with TLR4 signaling. This is the first report to identify signaling pathways used by gC1qR-mediated immune suppression, and it establishes a means of complement-mediated immune suppression to inhibit Th1 immunity crucial for clearing pathogenic infection.
Waggoner
Stephen N
SN
Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville 22908, USA.
Cruise
Michael W
MW
Kassel
Rachel
R
Hahn
Young S
YS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D006801:Humans; D016753:Interleukin-10 / Q000502:physiology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008024:Ligands; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000276:immunology; D051379:Mice; D024101:Mitochondrial Proteins / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D014158:Transcription, Genetic / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology
D000911:Antibodies, Monoclonal; C087299:C1QBP protein, human; D002352:Carrier Proteins; D008024:Ligands; D008070:Lipopolysaccharides; D024101:Mitochondrial Proteins; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D018664:Interleukin-12; D019869:Phosphatidylinositol 3-Kinases