Involvement of TIR8 in immediate signalling events through the IL-1R/TLR family was investigated in primary cell types obtained from TIR8 deficient mice [22, 27]. Enhanced responses to IL-1 and LPS but not to TNF were observed in kidney cells and splenocytes , but not in bone marrow derived macrophages, as expected on the basis of undetectable TIR8 expression in this cell type. Immature DC, which among the myelomonocytic lineage are the cells that selectively express TIR8, were investigated in detail. TIR8-deficient DC, but not macrophages, showed increased responsiveness to LPS and CpG oligodeoxynucleotides in terms of production of cytokines and chemokines (IL-6, CXCL10, IL-12, IL-10) . LPS and CpG interact with signalling receptor complexes which include TLR4 and TLR9, respectively . The finding that TIR8-deficient DC show increased responsiveness to TLR agonists is consistent with its pattern of expression and its proposed function as a negative regulator of IL-1R/TLR signalling. Moreover, given the sentinel function of DC and their localisation at epithelial surfaces, the expression of TIR8 in this cell type is consistent with the view that this molecule has a regulatory role in epithelial tissues and at mucosal sites (see below). Therefore, the negative regulatory function of TIR8 is likely to be cell-type specific, given its differential expression in different cell types.
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