Anti-IL12A monoclonal antibody, clone C-U32 Functional Grade

Interactions between genetic variation and environmental factors have been invoked in schizophrenia genesis, but pathways linking them are uncertain. We used a pathway-oriented approach to evaluate six genes mediating IL18 function (IL-18, IL18BP, IL18R1, IL18RAP, IL12B, and IL12A). The first five are also localized to regions previously linked with schizophrenia. Fifty-four representative tag SNPs were selected from comprehensive sequence data and genotyped in 478 patients with schizophrenia/schizoaffective disorder (DSM IV criteria) and 501 unscreened control individuals. Exposure to three herpes viruses previously suggested as risk factors for schizophrenia was estimated simultaneously among the cases. Five SNPs in four genes were associated with schizophrenia, most prominently rs2272127 at IL18RAP (P = 0.0007, odds ratio for C allele 1.49, 95% CI: 1.18-1.87; P = 0.03 following correction for multiple comparisons). Exploratory analysis revealed that rs2272127 was also associated with herpes simplex virus 1 (HSV1) seropositivity in cases (P = 0.04, OR for G allele 1.58, 95% CI: 1.04-2.39). Similar patterns were observed at another correlated SNP (rs11465702, P = 0.005 and 0.006, respectively for associations with schizophrenia and HSV1 seropositivity). We suggest plausible, testable hypotheses linking IL-18 signaling and HSV1 in schizophrenia pathogenesis. (C) 2007 Wiley-Liss, Inc.

STAT4, which is activated mainly by IL-12, promotes inflammatory responses by inducing Th1 and Th2 cytokines. Recent genome-wide association studies indicate that STAT4 gene variants are associated with risk of various types of liver diseases, but how STAT4 contributes to liver disease pathogenesis remains obscure. In this study, STAT4 activation was detected in liver immune cells from patients with viral hepatitis and autoimmune hepatitis, as well as in a mouse model of concanavaLin A (Con A)-induced hepatitis. Such STAT4 activation was detected mainly in T cells, natural killer T cells, and macrophages and Kupffer cells, and was diminished in I112a/and 11/26/mice. As expected, disruption of the Stat4 gene reduced production of Th1 and Th2 cytokines, but surprisingly exacerbated Con A-induced liver injury. Similarly, disruption of IL12a or 11126 also augmented Con A-induced hepatocellular damage. Further studies showed that hepatic natural killer T (NKT) cells from Con A-treated Stat4(-/-) mice had higher levels of FasL expression and increased cytotoxicity against hepatocytes than those from Con A-treated WT mice. In vitro, blocking FasL attenuated Stat4(-/-) NKT cytotoxicity against hepatocytes. In conclusion, despite up-regulation of proinflammatory cytokines, STAT4 protects against acute T-cell hepatitis, which is mediated by direct or indirect down-regulation of FasL expression on NKT cells.