Involvement of interleukin-8 in dialysis-related arthritis

Involvement of interleukin-8 in dialysis-related arthritis. To elucidate the role of interleukin (IL)-8, a chemotactic factor for neutrophils, in dialysis-related arthritis (DRA) of patients on long-term hemodialysis, the concentration of IL-8 was measured in the synovial fluids of DRA patients with acute arthralgia and joint swelling, and was compared with those in patients with rheumatoid arthritis (RA) and patients with osteoarthritis (OA). We noted a marked elevation of IL-8 in the joint fluids of patients with DRA and RA as compared with OA. Furthermore, to determine the role of IL-8 in synovitis, we examined the in vivo effect of intra-articular injection of human recombinant IL-8 on leukocyte infiltration into the joint space of rabbits. A single injection of IL-8 to the joints of rabbits induced rapid infiltration of neutrophils into the joint space and synovial tissues, which reached a maximum in four hours. The oral administration of indometacin farnesil (a prodrug that is converted to indomethacin after intestinal absorption) before the injection of IL-8 alleviated the infiltration of neutrophils. When human synovial cells were incubated with tumor necrosis factor (TNF)-α, the expression of IL-8 mRNA and IL-8 production in the cultured synovial cells were increased. The TNF-α-stimulated expression of IL-8 mRNA and IL-8 production in the cultured synovial cells were markedly inhibited by dexamethasone. In conclusion, IL-8 levels were markedly elevated in the joint fluids of patients with DRA. Interleukin-8 released from synovial cells may be an important factor to induce acute inflammation in DRA. Dexamethasone and indomethacin may be effective for DRA by inhibiting the production and chemotactic actions of IL-8, respectively

Clinical Significance of Telomerase Activity and Telomere Length in Various Liver Diseases

We investigated the clinical significance of telomerase activity and telomere length in hepatocellular carcinomas (HCCs) and chronic liver diseases. Telomerase activity was assessed quantitatively using \u27Stretch PCR\u27 assay and telomere length by Southern blotting in 24 HCCs, 2 focal nodular hyperplasia, 8 liver cirrhosis, 10 chronic hepatitis and 8 histologically normal livers. The latter were obtained from normal sections of resected specimens of cholangiocellular carcinoma, metastatic liver tumor or hemangioma. The relative titers of telomerase activity (RTA) were significantly higher in HCCs (average, 54 units) than in chronic liver diseases (average, 0.6 units) (P<0.001). In comparison, RTA was less than 2 units in non-malignant liver tissues. Telomere length in cirrhotic liver tissues was significantly shorter than in normal livers and tended to be shorter than those in chronic hepatitis. Telomere length and RTA correlated with the grading of tissue derangement in chronic liver diseases. Our results suggest that RTA estimated by Stretch PCR assay might be clinically useful for accurate diagnosis of liver diseases, particularly HCCs. In addition, telomere length seems to having a possibility as a useful predictor for risk of hepatocarcinogenesis

G9a regulates group 2 innate lymphoid cell development by repressing the group 3 innate lymphoid cell program.

Innate lymphoid cells (ILCs) are emerging as important regulators of homeostatic and disease-associated immune processes. Despite recent advances in defining the molecular pathways that control development and function of ILCs, the epigenetic mechanisms that regulate ILC biology are unknown. Here, we identify a role for the lysine methyltransferase G9a in regulating ILC2 development and function. Mice with a hematopoietic cell-specific deletion of G9a (Vav.G9a(-/-) mice) have a severe reduction in ILC2s in peripheral sites, associated with impaired development of immature ILC2s in the bone marrow. Accordingly, Vav.G9a(-/-) mice are resistant to the development of allergic lung inflammation. G9a-dependent dimethylation of histone 3 lysine 9 (H3K9me2) is a repressive histone mark that is associated with gene silencing. Genome-wide expression analysis demonstrated that the absence of G9a led to increased expression of ILC3-associated genes in developing ILC2 populations. Further, we found high levels of G9a-dependent H3K9me2 at ILC3-specific genetic loci, demonstrating that G9a-mediated repression of ILC3-associated genes is critical for the optimal development of ILC2s. Together, these results provide the first identification of an epigenetic regulatory mechanism in ILC development and function