Send to

Choose Destination
Immunity. 2005 Apr;22(4):415-26.

C5a negatively regulates toll-like receptor 4-induced immune responses.

Author information

Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center and College of Medicine, University of Cincinnati, Cincinnati, Ohio 45229, USA.


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.

[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center