The maximum chance to respond favourably was observed when patients carried either AGCC GATA, whereas patients responded moderately or not when carrying GGCC (Table 3; S1 File). Open in a separate window Fig 5 Allele distribution subject to etanercept response.Bars represent minor allele frequencies of IL-10C2849 G A, -1082 G A, -819 C T, and -592 C A in RA patients responding well, or moderately/not to etanercept therapy. identified the four predominant haplotypes AGCC, GATA, GGCC, and GACC in almost equal distribution. Patients that responded well carried the putative IL-10 low producer allele -2849 A or the haplotypes AGCC and GATA (RR 2.1 and 4.0, respectively; 95% CI 1.1C4.0 and 1.1C14.8), whereas an unfavourable response was associated with carriage of the putative high producer haplotype GGCC (RR 1.9, 95% CI 1.1C3.3). No significant associations of alleles or haplotypes with disease susceptibility were observed. In RA, a low IL-10 production which is genetically Mazindol determined rather by haplotypes than by SNPs may favour the response to etanercept treatment. Iatrogenic blockade of TNF may reveal proinflammatory effects of its endogeneous antagonist IL-10. Further studies are needed to correlate these genetic findings to direct cytokine measurements. Introduction The introduction of tumor necrosis factor (TNF) blocking agents into the therapy of rheumatoid arthritis (RA) is a story of remarkable success [1]. The efficacy of anti-TNF is comparable to or even better than methotrexate, and today, we are not aware of startling safety concerns. Additionally, antagonizing cytokines provided us with detailed insights into the pathophysiology of chronic inflammation [2]. However, about 30C40% of the patients fail to respond. Moreover, response to inhibitors with different mechanisms of action such as soluble receptors or monoclonal antibodies is heterogeneous. Compared to patients on conventional DMARD therapy, patients treated with anti-TNF seem to have a higher risk of serious infections, of tuberculosis, of infections by herpes zoster, and also the risk of melanoma seems to be slightly increased [3]. Thus, reliable predictors of therapy outcome are expedient, allowing for the rational selection of eligible patients. Explicit immunological consequences of blocking TNF are not yet certain, as complex interactions within the cytokine network that support the ongoing inflammation are not fully understood. However, the balance of pro- and anti-inflammatory cytokines has been attributed an important role [4, 4]. In contrast to TNF-alpha, interleukin-10 (IL-10) is considered to mediate down-regulation of the inflammatory cascade, as it inhibits the activation and effector functions of T cells, macrophages, and monocytes [5, 6]. In particular, it acts as a negative autocrine regulator of TNF-alpha and other pro-inflammatory cytokines [7]. A direct anti-inflammatory potential of IL-10 in cartilage has been described [8]. On the other hand, effects of IL-10 are pleiotropic, as it stimulates B cell survival, proliferation, differentiation, and antibody isotype Mazindol switching [6]. Elevated levels of IL-10 have been found in the serum and synovial fluid of RA patients, possibly contributing to the diminished T cell function and increased antibody and rheumatoid factor production [9]. In Rabbit Polyclonal to DNA Polymerase lambda fact, IL-10 has been reported to activate B cells to promote autoantibody production like rheumatoid factor or antibodies against cyclic citrullinated peptide [10C12]. Interindividual variability in IL-10 secretion is determined to a large scale by genetic variance [13]. The IL-10 promoter contains polymorphic elements that combine to form 4 major haplotype families [14]. Linkage disquilibrium restricts three proximal single nucleotide polymorphisms (SNPs) at -1082 A G, -819 T C, and -592 C A to assemble only three predominant haplotypes (ATA, ACC and GCC), which have been studied for their association with IL-10 production [15]. Homozygous carriers of GCC are considered as IL-10 high producers, emphasizing -1082 G as the most relevant allele [16C18]. Studies investigating a SNP at -2849 G A have shown that G carriers significantly Mazindol overproduce IL-10 [19, 20]. RA patients carrying -2849 G displayed higher autoantibody titres and a higher rate of joint destruction [21]. The relevance of this polymorphism as a part of extended haplotypes is not fully Mazindol understood. Based on theoretical considerations and experimental findings that attribute IL-10 a pathogenetic role in RA, the present study Mazindol addressed the question whether genetic polymorphisms associated with the constitutional IL-10 production could additionally be related to anti-TNF therapy response in RA. Potential genetic predictors of anti-TNF response have been reported [22]. We previously observed an association of IL-10 promoter microsatellites, that have also been linked to susceptibility to RA, with the outcome under etanercept therapy [23, 24]. We now genotyped patients and healthy controls for the IL-10 promoter SNPs at -2849, -1082, -819, and -592, reconstructed haplotypes, and analyzed their association with response.