It is well established that IL-18R- and toll-like receptor (TLR)-mediated signalings share a common signal pathway mediated by signal adaptor, MyD88, and that IL-18 synergizes with IL-12 for IFN-gamma production by NK cells. Here, we investigated whether TLR agonists can replace IL-18 for production of IFN-gamma by NK cells. Freshly isolated NK cells possessed functional LPS receptor composed of TLR4/MD2 complex and of CD14, and also expressed other various tlrs. Hepatic CD3(-)DX5(+) NK cells produced IFN-gamma in response to TLR2 or TLR7 agonists only when co-stimulated with IL-12, indicating that TLR agonists synergize with IL-12 for IFN-gamma. The tlr2(-/-) or tlr7(-/-) NK cells could not produce IFN-gamma in response to IL-12 plus TLR2 or TLR7 ligands, respectively, indicating requirement of the corresponding TLRs. Furthermore, upon stimulation with these combinations, wild-type NK cells produced type 1 chemokines, such as CCL3, CCL4 and CCL5 as well. NK cells from bacterium (e.g. Propionibacterium acnes)-inoculated rag2(-/-) mice, when compared with those from naive mice, exhibited significantly enhanced capacity to produce these CC chemokines and IFN-gamma, suggesting that microbial infection enhances responsiveness of NK cells to TLR agonists. These results indicate that upon microbial infection, macrophages produce IL-12 that renders NK cells highly responsive to TLR agonists to produce IFN-gamma and chemokines, which might in turn recruit and fully activate macrophages, leading to the development of inflammatory foci presumably necessary for efficient microbial eradication. Thus, NK cells, like T cells, induce orchestrated immune responses in collaboration with macrophages to show potent host defense effects during early infectious phase.

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Background Declining proportions of male births have been reported in several industrialised countries. Previous reports have shown that exposure to certain chemical substances might influence the secondary sex ratio (SSR). We assessed the associations between paternal occupational exposure to chemicals and the SSR of their children using the Japan Environment and Children's Study (JECS), a large-scale birth cohort study.Methods Data on paternal occupational exposure to various agents and other covariates were collected using a selfadministered questionnaire to partners of pregnant female participants enrolled in the JECS. After adjusting for potential confounders, multivariable modified Poisson regression models were used to evaluate associations between paternal occupational exposures and the SSR of their children. This study was registered in the UMIN Clinical Trials Registry, number UMIN000030786. FindingsThe JECS study gathered data on 103 062 pregnancies, 104 065 fetuses, and 51 898 partners of pregnant women. Among 50 283 children with data on paternal occupational exposures, 25 657 were male and 24 626 were female. The proportion of boys whose fathers were regularly occupationally exposed to insecticides was 0•445 (males, n=293; females, n=366; 95% CI 0•406-0•483), which was lower than the proportion of boys whose fathers were not exposed to insecticides. After adjusting for confounding factors, regular paternal occupational exposure to insecticides (adjusted relative risk 0•86, 95% CI 0•78-0•96) and medical disinfectants (0•95, 0•90-1•00) were significantly associated with lower SSRs among their offspring compared with the offspring of fathers not exposed to these substances.Interpretation A declining proportion of boys could potentially be due to fathers working in environments in which they are exposed to chemicals. The associations between poorer semen quality and levels of reproductive and thyroid hormones require investigation.Funding Ministry of the Environment of Japan.

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Membranous Nephropathy (MN) is classified as idiopathic or secondary, with the known causes of secondary MN including the following : infections, autoimmune diseases, drug reactions and malignancies. Idiopathic membranous nephropathy (IMN) is more frequently than secondary in Japanese children. We retrospectively reviewed 27 children (20 boys, 7 girls) with membranous nephropathy in our hospital for the period of 1985 to 2005, aged 8.1 +−3.9 years at onset. 17 patients are idiopathic membranous Nephropathy (IMN), 10 patients are hepatitis B virus related membranous nephropathy (HBMN) that is the most causes of secondary MN. In result, urinary abnormalities were detected in 16 patients through school urinary screening, and in other 11 children through chance urinary abnormalities. Six patients had nephrotic syndrome at onset. Electron microscopic staging according to the classification by Ehrenreich and Churg was performed in all patients. IMN consists of stage in 4, in 9, and III in 4, while HBMN consist of stage I in 3, II in 6, and III in 4. Oral corticosteroid was given to 17 patients, immunosuppressive therapy with cyclosporin was administered to only one patients. In spite of treatment with corticosteroid or not, almost IMN patients showed complete remission of proteinuria at the follow-up of 10 years, and only one patient had isolated mild hematuria. From these results, we suggest that IMN and HBMN in Japanese children might take a better course and outcome than IMN in adults and non-Japanese children.