Objective. The results of a recent genome-wide association study have shown that ERAP1 and IL23R are associated with ankylosing spondylitis (AS) in Caucasian populations from North America and the UK. Based on these findings, we undertook the current study to investigate whether single-nucleotide polymorphisms (SNPs) covering the genes ERAP1 and IL23R are associated with AS in a Han Chinese population.Methods. A case-control study was performed in Han Chinese patients with AS (n ‫؍‬ 527) and controls (n ‫؍‬ 945) from Shanghai and Nanjing. All patients met the modified New York criteria for AS. The Sequenom iPlex platform was used to genotype cases and controls for 21 tag SNPs covering IL23R and 38 tag SNPs covering ERAP1. Statistical analysis was performed using the Cochran-Armitage test for trend.Results. Multiple SNPs in ERAP1 were significantly associated with AS (for rs27980, P ‫؍‬ 0.0048; for rs7711564, P ‫؍‬ 0.0081). However, no association was observed between IL23R and AS (for all SNPs, P > 0.1). The nonsynonymous SNP in IL23R, rs11209026, widely thought to be the primary AS-associated SNP in IL23R in Europeans, was found not to be polymorphic in Chinese.Conclusion. Our results demonstrate that genetic polymorphisms in ERAP1 are associated with AS in Han Chinese, suggesting a common pathogenic mechanism for the disease in Chinese and Caucasian populations, and that IL23R is not associated with AS in Chinese, indicating a difference in the mechanism of disease pathogenesis between Chinese and Caucasian populations. This may result from the fact that rs11209026, the nonsynonymous SNP in IL23R, is not polymorphic in Chinese patients, providing further evidence that rs11209026 is the key polymorphism associated with AS (and likely inflammatory bowel disease and psoriasis) in this gene.

Low to moderate alcohol consumption inversely associated with the development of RA in a manner that appears to be dose-dependent, time-dependent and sex-dependent. Large prospective studies that investigate gene-environment interactions are required to further clarify the aetiology of RA.

Sepsis results from a dysregulation of the regulatory mechanisms of the pro-and anti-inflammatory response to invading pathogens. The mitogen-activated protein (MAP) kinase cascades are key signal transduction pathways involved in the cellular production of cytokines. The dual-specific phosphatase 1 (DUSP 1), mitogen-activated protein kinase phosphatase-1 (MKP-1), has been shown to be an important negative regulator of the inflammatory response by regulating the p38 and Jun N-terminal protein kinase (JNK) MAP kinase pathways to influence pro-and anti-inflammatory cytokine production. MKP-2, also a dual-specific phosphatase (DUSP 4), is a phosphatase highly homologous with MKP-1 and is known to regulate MAP kinase signaling; however, its role in regulating the inflammatory response is not known. We

IL-8 is a key mediator in the pathophysiology of acute lung injury. TNFalpha stimulates IL-8 production in respiratory epithelial cells by activating both the NF-kappaB and MAP kinase pathways. The precise mechanism by which these pathways are downregulated to terminate IL-8 production remains unclear. We studied the regulatory role of the serine/threonine phosphatase, PP2A, on the signaling pathways involved in IL-8 production from respiratory epithelial cells. Inhibition of PP2A using okadaic acid or gene knockdown using siRNA resulted in an augmentation of TNFalpha-induced IL-8 production. We also found that PP2A inhibition resulted in prolonged activation of JNK, p38, and ERK resulting in both increased transcriptional activation of the IL-8 promoter and posttranscriptional stabilization of IL-8 mRNA. Because TNFalpha had been shown to activate ceramide accumulation, and separate studies had linked ceramide with activation of PP2A, we hypothesized the pathway of TNFalpha-inducing ceramide to activate PP2A comprised an endogenous regulatory pathway. Inhibition of the immediate sphingomyelinase-dependent pathway as well as the de novo synthesis pathway of ceramide production reduced serine/threonine phosphatase activity and augmented IL-8 production. These data suggest that ceramide plays a role in activating PP2A to terminate ongoing IL-8 production. In summary, our data suggest that in respiratory epithelium, TNFalpha induces ceramide accumulation, resulting in subsequent activation of PP2A, which targets those kinases responsible for transcriptional activation of IL-8.