Toll-like receptor signalling pathways as key targets for mediating the anti-inflammatory and immunosuppressive effects of glucocorticoids

Abstract

Toll-like receptors (TLRs) play crucial roles in the induction of innate immune responses by recognising pathogen-associated molecular patterns. The engagement of TLRs by pathogens results in induction of co-stimulatory molecules that facilitate a specific immune response and also in the induction of pro-inflammatory proteins that will promote the elimination of pathogens from the body. TLRs employ many of the same signalling components as the type I interleukin (IL)-1 receptor (IL-1R). This is hardly surprising since the intracellular regions of TLRs and the IL-1R share a conserved Toll/IL-1R homology domain (TIR) that allows the receptors to recruit the intracellular TIR-containing adaptor protein Myd88. The latter then activates IL-1R-associated kinases that in turn recruit well-characterised downstream effectors culminating in activation of MAP kinases and transcription factors such as NFkappaB and AP-1. Since glucocorticoids are known to target the latter transcription factors and the MAP kinase cascades, this commentary highlights the likely crucial importance of Toll-like receptor signalling pathways as key targets for mediating the anti-inflammatory and immunosuppressive effects of steroids.