C5a negatively regulates toll-like receptor 4-induced immune responses.
The complement system and the Toll-like receptors (TLRs) are two central arms of innate immunity that are critical to host defense as well as the development of adaptive immunity. Most pathogens activate both complement and TLRs, suggesting the potential for crosstalk between the two systems. We show here that the complement-derived C5a anaphylatoxin negatively regulates TLR4- and CD40-induced synthesis of IL-12 family cytokines (IL-12, IL-23, and IL-27) from inflammatory macrophages (M phi s) by extracellular signal-regulated kinase- and phosphoinositide 3 kinase-dependent pathways. This decreased cytokine response translates into a decreased T helper type 1 (Th1) response in vitro and in vivo. Accordingly, we found enhanced Th1 immunity in C5a receptor-deficient mice, something that conferred protection from Leishmania major infection. Our findings identify the negative impact of C5a on IL-12 family cytokines as an important mechanism for regulating Th1 polarization in response to innate and adaptive immune network activation.
Hawlisch
Heiko
H
Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center and College of Medicine, University of Cincinnati, Cincinnati, Ohio 45229, USA.
Belkaid
Yasmine
Y
Baelder
Ralf
R
Hildeman
David
D
Gerard
Craig
C
Köhl
Jörg
J
D000818:Animals; D001483:Base Sequence; D015936:Complement C5a / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D018664:Interleukin-12 / Q000096:biosynthesis; D007891:Leishmania / Q000472:pathogenicity; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015854:Up-Regulation; D000099185:Interferon Regulatory Factor-8
D015936:Complement C5a; D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D018664:Interleukin-12; D008562:Membrane Glycoproteins; D048052:Mitogen-Activated Protein Kinase 3; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D000099185:Interferon Regulatory Factor-8; C494258:Irf1 protein, mouse