Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors

Abstract

The activation of Toll-like receptors (TLRs) is central to innate and adaptive immunity. All TLRs use the adaptor MyD88 for signalling, but the mechanisms underlying the MyD88-mediated gene induction programme are as yet not fully understood. Here, we demonstrate that the transcription factor IRF-5 is generally involved downstream of the TLR-MyD88 signalling pathway for gene induction of proinflammatory cytokines, such as interleukin-6 (IL-6), IL-12 and tumour-necrosis factor-alpha. In haematopoietic cells from mice deficient in the Irf5 gene (Irf5-/- mice), the induction of these cytokines by various TLR ligands is severely impaired, whereas interferon-alpha induction is normal. We also provide evidence that IRF-5 interacts with and is activated by MyD88 and TRAF6, and that TLR activation results in the nuclear translocation of IRF-5 to activate cytokine gene transcription. Consistently, Irf5-/- mice show resistance to lethal shock induced by either unmethylated DNA or lipopolysaccharide, which correlates with a marked decrease in the serum levels of proinflammatory cytokines. Thus, our study identifies IRF-5 as a new, principal downstream regulator of the TLR-MyD88 signalling pathway and a potential target of therapeutic intervention to control harmful immune responses.

TLR signalling and activation of IRFs: revisiting old friends from the NF-κB pathway

“…By contrast, the induction of IFN-a by TLR9 in plasmacytoid DCs from these mice is unaffected. Takaoka et al [61] propose that IRF5 is involved selectively in the induction of proinflammatory cytokines by virtually all TLRs and this is consistent with the increased resistance of Irf5 K/K mice to lethal shock induced by unmethylated DNA and LPS. Furthermore, putative IRF5-binding sites are identifiable in the promoters of several genes encoding proinflammatory cytokines.…”

“…IRF5 associates with both Myd88 and TRAF-6 and ligands for TLR4 and TLR9 promote nuclear translocation of IRF5 in a Myd88-dependent manner [61] (Figure 3). However, many of the downstream mediators of the IRF5 pathway await identification.…”

“…A recent report has emphasized an important role for another member of the IRF family, IRF5, in TLR signalling [61]. The induction of proinflammatory cytokines, such as TNF, IL-6 and IL-12, by TLR3, TLR4, TLR5, TLR7 and TLR9 ligands is impaired severely in various cells from IRF5-deficient mice.…”

Interferon regulatory factor-5 is genetically associated with systemic lupus erythematosus in African Americans

“…7,8 Patients with SLE often show increased expression of interferon (IFN)-inducible genes, the presence of which can correlate with more severe disease manifestations such as neurological, renal or hematological involvement. 9 Interferon regulatory factor-5 (IRF5), a transcription factor, regulates the expression of IFN-a genes, 10,11 thus making it a good candidate gene for SLE susceptibility. Recent publications have reported a significant association between single nucleotide polymorphisms (SNPs) and haplotypes of IRF5 and SLE, both in familyand population-based studies of patients from multiple ethnicities [12][13][14][15][16][17][18][19][20][21] (including meta-analyses) 16 ; however, these studies have not examined African Americans.…”

Association of IRF5 polymorphisms with systemic lupus erythematosus in a Japanese population: Support for a crucial role of intron 1 polymorphisms

“…It is involved in the induction of IFN and proinflammatory cytokines. In mice deficient in the Irf5 gene, the production of type I IFN against viral infections was found to be decreased and the induction of proinflammatory cytokines by Toll-like receptor (TLR) stimulation was found to be impaired (16,17). In humans, overexpression of IRF5 was shown to stimulate the expression of type I IFN genes after viral infection, while knockdown of IRF5 by short interfering RNA was shown to reduce the induction of type I IFN in response to TLR-7 ligand (18,19).…”