Abstract
Influenza viruses of avian origin continue to pose pandemic threats to human health. Some of the H5N1 and H9N2 virus subtypes induce markedly elevated cytokine levels when compared with the seasonal H1N1 virus. We previously showed that H5N1/97 hyperinduces tumor necrosis factor (TNF)-alpha through p38 mitogen activated protein kinase (MAPK). However, the detailed mechanisms of p38MAPK activation and TNF-alpha hyperinduction following influenza virus infections are not known. Negative feedback regulations of cytokine expression play important roles in avoiding overwhelming production of proinflammatory cytokines. Here we hypothesize that protein phosphatases are involved in the regulation of cytokine expressions during influenza virus infection. We investigated the roles of protein phosphatases including MAPK phosphatase-1 (MKP-1) and protein phosphatase type 2A (PP2A) in modulating p38MAPK activation and downstream TNF-alpha expressions in primary human monocyte-derived macrophages (PBMac) infected with H9N2/G1 or H1N1 influenza virus. We demonstrate that H9N2/G1 virus activated p38MAPK and hyperinduced TNF-alpha production in PBMac when compared with H1N1 virus. H9N2/G1 induced PP2A activity in PBMac and, with the treatment of a PP2A inhibitor, p38MAPK phosphorylation and TNF-alpha production were further increased in the virus-infected macrophages. However, H9N2/G1 did not induce the expression of PP2A indicating that the activation of PP2A is not mediated by p38MAPK in virus-infected PBMac. On the other hand, PP2A may not be the targets of H9N2/G1 in the upstream of p38MAPK signaling pathways since H1N1 also induced PP2A activation in primary macrophages. Our results may provide new insights into the control of cytokine dysregulation.
Highlights
Influenza viruses continue to pose pandemic and epidemic threats to the public
We have previously demonstrated that H5N1/97 virus hyperinduces tumor necrosis factor (TNF)-alpha expression in primary monocyte-derived macrophages (PBMac), which is mediated by p38 mitogen activated protein kinase (MAPK) [10]
Our previous reports demonstrate that avian influenza viruses including H5N1 and H9N2 Quail/HK/G1/97 (H9N2/G1) induce high levels of TNF-alpha production in macrophages in contrast to those cells infected with human influenza virus subtypes H3N2 and H1N1 [10,11]
Summary
Influenza viruses continue to pose pandemic and epidemic threats to the public. Infection of humans with the highly pathogenic avian influenza H5N1 virus is associated with mortality in excess of 60% [1]. MAPK signaling pathways play key roles in the induction of inflammatory reactions including production of proinflammatory cytokines such as TNF-alpha, IL-1β and IL-6. Macrophages from MKP-1 deficient mice show prolong activation of p38MAPK and enhanced production of TNF-alpha and IL-6 [15]. The roles of MKP-1 and PP2A in cytokine regulation during influenza virus infections have not been reported. The phosphorylation levels of p38MAPK and subsequent TNF-alpha expression in H9N2/G1-infected macrophages were further increased by the treatment of a selective inhibitor of PP2A, okadaic acid (OA). OA increased the levels of p38MAPK phosphorylation and TNF-alpha mRNA in H1N1-infected macrophages These results provide insights into the complex mechanisms of MAPK-mediated cytokine production during influenza virus infections
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