Mammalian 2-Cys peroxiredoxin II (Prx II) is a cellular peroxidase that eliminates endogenous H2O2. The involvement of Prx II in the regulation of lipopolysaccharide (LPS) signaling is poorly understood. In this report, we show that LPS induces substantially enhanced inflammatory events, which include the signaling molecules nuclear factor κB and mitogen-activated protein kinase (MAPK), in Prx II–deficient macrophages. This effect of LPS was mediated by the robust up-regulation of the reactive oxygen species (ROS)–generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and the phosphorylation of p47phox. Furthermore, challenge with LPS induced greater sensitivity to LPS-induced lethal shock in Prx II–deficient mice than in wild-type mice. Intravenous injection of Prx II–deficient mice with the adenovirus-encoding Prx II gene significantly rescued mice from LPS-induced lethal shock as compared with the injection of a control virus. The administration of catalase mimicked the reversal effects of Prx II on LPS-induced inflammatory responses in Prx II–deficient cells, which suggests that intracellular H2O2 is attributable, at least in part, to the enhanced sensitivity to LPS. These results indicate that Prx II is an essential negative regulator of LPS-induced inflammatory signaling through modulation of ROS synthesis via NADPH oxidase activities and, therefore, is crucial for the prevention of excessive host responses to microbial products.

ObjectivesThe present study evaluated the effects of job stress, including organisational system to self-rated depression through a panel study of male municipal firefighters in the Republic of Korea.MethodsA panel of 186 municipal firefighters reported self-rated depressive symptoms according to the Beck Depression Inventory (BDI). The effects of job stress were evaluated using the Korea Occupational Stress Scale, taken one year earlier and classified by the median value. Panel members were classified into Depression or Control groups according to BDI scores, with a cut-off level of ‘over mild depression’ in a follow-up survey.ResultsThe Depression group included 17 (9.1%) workers. Firefighters who scored high on occupational system had an 8.3 times greater risk of being assigned to the Depression group than those who had not (adjusted odds ratio [OR] = 8.03, 95% confidence interval (CI) = [1.73–37.22]). In contrast, job stress from a ‘difficult physical environment’ revealed negative risks related to being classified in the Depression group (AOR = 0.20, 95% CI = [0.04–0.92]).ConclusionsAlthough the healthy worker effect may be involved, job stress based on perceptions of organisational system was a strong risk factor for depression. A comprehensive approach should be considered that encompasses social issues when assessing or mental health in high-risk groups, as well as the practical issue of physiochemical hazards.

Mycobacterium bovis bacillus Calmette-Gué rin (BCG) induces innate immune responses through Toll-like receptor (TLR) 2 and TLR4. We investigated the role of apoptosis-regulating signal kinase (ASK) 1 in reactive oxygen species (ROS)-mediated innate immune responses induced by BCG mycobacterial infection. In macrophages, M. bovis BCG stimulation resulted in rapid activation of mitogen-activated protein kinases (MAPKs), secretion of inflammatory cytokines, such as tumor necrosis factor (TNF)-a and interleukin (IL)-6, and ROS generation in a TLR2-and TLR4-dependent manner. M. bovis BCG-induced ROS production led to robust activation of ASK1 upstream of the c-jun-N-terminal kinase and p38 MAPK, but not extracellularregulated kinase 1/2. Blocking ASK1 activity markedly attenuated M. bovis BCG-induced TNF-a and IL-6 production by macrophages. Both TLR2 and TLR4 were required for optimal activation of ASK1 in response to M. bovis BCG. Furthermore, we present evidence that TNF receptor-associated factor (TRAF) 6 activities were essential for ROS-mediated ASK1 activation by M. bovis BCG. Finally, ASK1 activities were required for effective control of intracellular mycobacterial survival. Thus, the results of this study suggest a novel role of the TLR-ROS-TRAF6-ASK1 axis in the innate immune response to mycobacteria as a signaling intermediate. Keywords: Mycobacterium bovis bacillus Calmette-Guérin; apoptosis-regulating signal kinase 1; Toll-like receptor; reactive oxygen species; macrophages; innate immunityThe Mycobacterium bovis bacillus Calmette-Guérin (BCG) strain is a tuberculosis (TB) vaccine strain that is almost nonpathogenic, but retains the immunogenic properties of TB. 1 M. bovis BCG serves as an immune potentiator of lymphocytes through the maturation of dendritic cells. Infection of dendritic cells with M. bovis BCG or M. TB facilitates the secretion of inflammatory cytokines, including tumor necrosis factor (TNF)-a, interleukin (IL)-1b, and IL-12, and upregulation of a variety of costimulatory molecules. 2,3 Previously, it was demonstrated that higher susceptibility to TB was correlated with impaired proinflammatory responses to M. bovis BCG components in mice with respiratory infections. 4 Stimulation of Toll-like receptors (TLRs) induces the production of antimicrobial peptides and proinflammatory cytokines through nuclear factor-kB (NF-kB) and other signaling pathways, thereby playing a central role in the link between innate and adaptive immunity. 5,6 Mitogen-activated protein kinase (MAPK) pathways are crucial to macrophage signaling induced by mycobacteria through TLRs. 7,8 In MAPK signaling cascades, MAPK kinase kinase (MAPKKK) activates MAPK kinase (MAPKK), which subsequently activates MAPK. 9 Apoptosis signal-regulating kinase1 (ASK1) is a member of the MAPKKK family, which activates two different MAPK cascades, the SEK1/MKK7-JNK and MKK3/MKK6-p38 MAPK pathways. 10,11 Overexpression of wild-type (WT) or the constitutively active form of ASK1 induces apoptosis in various cell types. 10,11 In contras...

Background: Anemia is a common extraintestinal manifestation of inflammatory bowel disease (IBD). However, data on the influence of anti-tumor necrosis factor-alpha (anti-TNF-α) agents and iron supplementation on anemia in patients with IBD are sparse. We assessed the effect of iron supplementation in patients with IBD initially treated with an anti-TNF-α agent. Methods: Data from 79 IBD patients who started anti-TNF-α treatment at a tertiary hospital were analyzed. The patients were divided into the anti-TNF-α ( n = 52) and anti-TNF-α with iron supplementation ( n = 27) groups. Effects on laboratory parameters, the prevalence of anemia, and disease activity were evaluated at baseline (year 0) and 1 year later. Results: The hemoglobin (Hb) level significantly increased between years 0 and 1 in both groups [12.0 ± 1.8–13.3 ± 2.0 g/dL in the anti-TNF-α group ( p < 0.001) and 9.8 ± 2.4–11.7 ± 2.3 g/dL in the anti-TNF-α and iron supplementation group ( p = 0.004)]. In a subgroup analysis of severely anemic patients with IBD, iron supplementation increased the magnitude of the improvement in Hb level (8.5 ± 1.5–11.4 ± 2.1 g/dL; p = 0.001) compared with the anti-TNF-α group (9.3 ± 0.8–11.4 ± 2.7 g/dL; p = 0.081). Disease activity was significantly improved in both groups at year 1 compared with year 0. Persistent anemia was significantly correlated with severe anemia at baseline ( p = 0.017). Conclusion: In anemic patients with IBD, anti-TNF-α agents led to clinically meaningful improvements in anemia independent of iron supplementation. Also, iron supplementation could be helpful in severely anemic patients with IBD.

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