However, influx of Th1 and innate immune cells was not compromised in the absence of IL-23. IL-22 and IL-23 play either redundant or minimal roles in the pathogenesis of Chlamydia infection in the mouse model. Induction of Th17-associated cytokines by a Chlamydia vaccine should be avoided as these responses are not central to resolution of infection and have pathologic potential. “
“There is limited

insight into the mechanisms involved in the counterregulation of TLR. Given the important role of TLR3/TIR domain-containing Trichostatin A mw adaptor-inducing IFN-β (TRIF)-dependent signalling in innate immunity, novel insights into its modulation is of significance in the context of many physiological and pathological processes. Herein, we sought to perform analysis to definitively assign a mechanistic role for MyD88 adaptor-like (Mal), an activator of TLR2/4 signalling, in the negative regulation of TLR3/TRIF signalling. Biochemical and functional analysis demonstrates that Mal negatively regulates TLR3, but not TLR4, mediated IFN-β

production. Co-immunoprecipitation experiments demonstrate that Mal associates with IRF7 (IRF, IFN regulatory factor), not IRF3, and Mal specifically blocks IRF7 activation. In doing so, Mal impedes TLR3 ligand-induced IFN-β induction. Interestingly, Mal does not affect the induction of IL-6 and TNF-α upon TLR3 ligand engagement. Together, these data show that the TLR adaptor Mal interacts with IRF7 and, in doing so, impairs Sitaxentan IFN-β induction through Trametinib the positive regulatory domains I-III enhancer element of the IFN-β gene following poly(I:C) stimulation. Our findings offer a new mechanistic insight into TLR3/TRIF signalling through a hitherto unknown mechanism whereby Mal inhibits poly(I:C)-induced IRF7 activation and concomitant IFN-β production. Thus, Mal is essential in restricting TLR3 signalling thereby protecting the host from unwanted immunopathologies associated with excessive IFN-β production. TLR are important

participants in the first line of defense against invading pathogens 1, 2. Upon ligand activation of the TLR, cytosolic Toll/IL-1 receptor (TIR) domain-containing adaptor proteins are recruited 1, of which, four activating adaptors have been identified, Myeloid differentiation factor 88 (MyD88), MyD88 adaptor-like (Mal)/Toll-IL-1 adaptor protein (TIRAP), TIR domain-containing adaptor-inducing IFN-β (TRIF) and TRIF-related adaptor molecule (TRAM). Despite the TLR having somewhat similar signal transduction pathways, there is specificity with regard to their adaptor usage 3. MyD88 is the common downstream adaptor that is recruited by all TLR except TLR3 4. Mal is required for signalling by TLR4 and TLR2 5, though it has recently been reported that Mal is not essential for TLR2 signalling 6.