IRAK1, a potential therapeutic target for rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disorder with hypertrophy, hyperplasia and angiogenesis of synovial tissue, which contribute to inflammatory joint destruction [1]. Although the exact causes of RA remain unknown, immunological dysregulation by inflammatory cytokines has been shown to be involved in driving the inflammation and synovial cell proliferation that characterize joint destruction in RA patients. Recently, Zhang et al. [2] found that IRAK1 rs3027898 C/A polymorphism was associated with risk of RA in a Chinese population. When the IRAK1 rs3027898 CC homozygote genotype was used as the reference group, the AA genotype was associated with significantly increased risk of RA. A significantly increased risk of RA associated with the IRAK1 rs3027898 AA genotype was more evident among anti-CCP positive patients compared with the IRAK1 rs3027898 CC/CA genotypes. Similarly, in a study in Greek, strong statistically significant difference was observed in IRAK1 rs3027898 A [ C polymorphism distribution between RA patients and controls, which was higher comparing the distribution of allele A versus allele C between the studied groups [3]. IRAK1 is a serine/threonine protein kinase implicated in the signaling cascade of the Toll/interleukin-1 receptor (TIR) family [4]. On Toll-like receptor (TLR) stimulation, IRAK1 is recruited and phosphorylated into the TLR signaling complex. Moreover, activation of MyD88 leads to phosphorylation of the IRAK1 in RA synovial fibroblasts (RASFs) [5]. After simulation with a TLR-2 ligand, PGN, increased mRNA expressions of IRAK1 and MyD88 were observed in RA fibroblast-like synoviocytes (RA-FLS). When treated with an anti-TLR-2 neutralizing antibody, IRAK1 and MyD88 mRNAs returned to baseline levels [6]. Repression of IRAK1 in THP-1 cells could also result in up to an 86 % reduction in tumor necrosis factor-a (TNF-a) production in RA patients [7]. Indeed, TNF-a was found to be associated with susceptibility to RA and with the presence of erosion in RA patients [8]. In addition, siRNA knockdown in monocytes reduced IRAK1 expression by *75 %. The siRNA-mediated reduction of IRAK1 impaired the ability of monocytes to produce TNF-a in response to IL-1b. Concomitantly, siRNA targeting of IRAK1 reduced IRAK1 mRNA levels by *65 % in Th17 cells, cytokine production of Th17 cells was even more profoundly affected [9]. Taken together, available evidence suggests a potential association of IRAK1 with RA. However, further studies are required to comprehensively explore the role of IRAK1 in RA, and the development of therapeutic agents targeting IRAK1 might result in important new, innovative therapies for RA.