Figure 1.

Complement regulation of TLR-induced cytokines of the IL-12 family. Activation of these complement receptors by their natural ligands downregulates TLR-induced mRNA expression of IL-12p35, IL-12/IL-23p40, IL-23p19 and IL-27p28 and production of bioactive IL-12, IL-23 and IL-27 [9,11,15,16,41,53]. The underlying signaling mechanisms involve induction of PI3K or ERK1/2 signaling, which in turn suppresses crucial transcription factors (IRF-1 and IRF-8), although the CD46 mechanism appears to be exerted at the post-transcriptional level. However, these receptors can also be activated by bacterial or viral pathogens, which thereby can manipulate TLR-induced IL-12 cytokines and associated T-helper responses in ways that interfere with protective immunity [35,41,53]. Although C5aR cannot be directly activated by pathogens, C5aR can come under pathogen control through microbial C5 convertase-like enzymes, which generate biologically active C5a [34]. The regulatory mechanisms shown appear to be cell-type specific and have been documented in human or mouse monocytes–macrophages.

Figure I. TLRs and their major ligands.

Figure I. Simplified representation of the complement cascade.