Diet-induced obesity dramatically reduces the efficacy of a 2009 pandemic H1N1 vaccine in a mouse model.

BACKGROUND: Obesity, a risk factor for increased severity of diverse diseases, is believed to have negative impact on vaccine efficacy. Recently, mortality has emerged as an outcome of pandemic influenza A virus subtype H1N1, necessitating development of effective vaccine strategies. Here we investigated effects of diet-induced obesity on vaccine-induced immune responses and protective efficacy against pandemic H1N1 influenza virus. METHODS: Diet-induced obese and lean C57BL/6J mice were immunized with commercial monovalent 2009 H1N1 vaccine, and antigen-specific antibody responses and neutralizing activities were observed. Following vaccination, mice were challenged with homologous H1N1 virus, and pathogenesis and mortality were examined. RESULTS: Vaccine-induced H1N1-specific antibody responses and neutralizing activities were markedly reduced in obese mice. Consistent with antibody responses, lung virus titers were significantly higher in obese mice than in lean controls after challenge. In addition, obese group showed greatly increased expression of proinflammatory cytokines and chemokines in lung tissue, severe lung inflammation, and higher eventual mortality rate (100%) compared with that among lean control mice (14%). CONCLUSIONS: Our results show that prophylactic immune responses and protectiveness induced by 2009 H1N1 vaccine could be extremely compromised in diet-induced obesity. These results suggest that novel vaccination strategies for high-risk groups, including the obese population, are required.

Wogonin suppresses TARC expression induced by mite antigen via heme oxygenase 1 in human keratinocytes. Suppressive effect of wogonin on mite antigen-induced TARC expression.

BACKGROUND: Mite antigen, extract from Dermatophagoides farinae in house dust, is a well-known causative agent of atopy or allergic diseases, which involves many inflammatory cytokines/chemokines expression. Heme oxygenase 1 (HO1) has recently emerged as an important cytoprotective enzyme against oxidative stress and inflammatory responses in many cell types. OBJECTIVE: The aim of this study was to investigate the possible mechanism by which wogonin, a natural product isolated from Scutellaria baicalensis, inhibited the mite antigen-induced chemokine expression in human keratinocytes, HaCaT cells. METHODS: The level of chemokine expression was measured by reverse transcription-polymerase chain reaction (RT-PCR) and signaling study was performed by Western blot analysis. RESULTS: The mite antigen-induced thymus- and activation-regulated chemokine (TARC/CCL17) expression in a dose-dependent manner via extracellular signal-regulated kinase (ERK) activation. However, it did not affect the expression of other chemokines including macrophage-derived chemokine (MDC/CCL22), RANTES, and IL-8. Interestingly, wogonin significantly suppressed the mite antigen-induced TARC expression via the induction of HO1. This suppression was completely restored by HO1 siRNA, suggesting a direct role of HO1 for the suppressive effect. Furthermore, exogenous CO, but not other end products of HO1 activity, also suppressed the mite antigen-induced TARC expression. CONCLUSION: Wogonin induces HO1 expression, which in turn HO1 and/or CO suppresses TARC expression induced by mite antigen in human HaCaT cells.

Carbon monoxide mediates heme oxygenase 1 induction via Nrf2 activation in hepatoma cells.

Carbon monoxide (CO) and nitric oxide (NO) are two gas molecules which have cytoprotective functions against oxidative stress and inflammatory responses in many cell types. Currently, it is known that NO produced by nitric oxide synthase (NOS) induces heme oxygenase 1 (HO1) expression and CO produced by the HO1 inhibits inducible NOS expression. Here, we first show CO-mediated HO1 induction and its possible mechanism in human hepatocytes. Exposure of HepG2 cells or primary hepatocytes to CO resulted in dramatic induction of HO1 in dose- and time-dependent manner. The CO-mediated HO1 induction was abolished by MAP kinase inhibitors (MAPKs) but not affected by inhibitors of PI3 kinase or NF-kappaB. In addition, CO induced the nuclear translocation and accumulation of Nrf2, which suppressed by MAPKs inhibitors. Taken together, we suggest that CO induces Nrf2 activation via MAPKs signaling pathways, thereby resulting in HO1 expression in HepG2 cells.