No abstract

Streptococcus pneumoniae (S. pneumoniae) causes high early mortality in pneumococcal pneumonia, which is characterized by acute lung injury (ALI). The molecular mechanisms underlying ALI and the high early mortality remain unknown. Despite recent studies that identify deubiquitinating enzyme cylindromatosis (CYLD) as a key regulator for T cell development, tumor cell proliferation, and NF-kappaB transcription factor signaling, its role in regulating bacteria-induced lethality, however, is unknown. Here, we showed that CYLD deficiency protected mice from S. pneumoniae pneumolysin (PLY)-induced ALI and lethality. CYLD was highly induced by PLY, and it inhibited MKK3-p38 kinase-dependent expression of plasminogen activator inhibitor-1 (PAI-1) in lung, thereby potentiating ALI and mortality. Thus, CYLD is detrimental for host survival, thereby indicating a mechanism underlying the high early mortality of pneumococcal pneumonia.

Background Diabetes mellitus (DM) is a major risk factor for cardiovascular mortality by increasing endothelial cell (EC) dysfunction and subsequently accelerating atherosclerosis. Extracellular-signal regulated kinase 5 (ERK5) is activated by steady laminar flow and regulates EC function by increasing eNOS expression and inhibiting EC inflammation. However, the role and regulatory mechanisms of ERK5 in EC dysfunction and atherosclerosis are poorly understood. Here, we report the critical role of the p90 ribosomal S6 kinase (p90RSK)/ERK5 complex in EC dysfunction in DM and atherosclerosis. Methods and Results Inducible EC-specific ERK5 knockout (ERK5-EKO) mice showed increased leukocyte rolling and impaired vessel reactivity. To examine the role of endothelial ERK5 in atherosclerosis, we used inducible ERK5-EKO-LDLR−/− mice and observed increased plaque formation. When activated, p90RSK associated with ERK5, and this association inhibited ERK5 transcriptional activity and up-regulated VCAM-1 expression. In addition, p90RSK directly phosphorylated ERK5 S496 and reduced eNOS expression. p90RSK activity was increased in diabetic mouse vessels, and FMK-MEA, a specific p90RSK inhibitor, ameliorated EC-leukocyte recruitment and diminished vascular reactivity in DM mice. Interestingly, in ERK-EKO mice, increased leukocyte rolling and impaired vessel reactivity were resistant to the beneficial effects of FMK-MEA, suggesting a critical role for endothelial ERK5 in mediating the salutary effects of FMK-MEA on endothelial dysfunction. FMK-MEA also inhibited atherosclerosis formation in ApoE−/− mice. Conclusions Our study highlights the importance of the p90RSK/ERK5 module as a critical mediator of EC dysfunction in DM and atherosclerosis formation, thus revealing a potential new target for therapeutic intervention.

Disturbed flow-mediated PKCζ–PIASy association is critical for p53 SUMOylation and induces p53 nuclear export and endothelial cell apoptosis.