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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Bacterial Proteins / genetics
-
Bacterial Proteins / metabolism
-
Bacterial Proteins / toxicity
-
Cysteine Endopeptidases / genetics
-
Cysteine Endopeptidases / physiology*
-
Deubiquitinating Enzyme CYLD
-
Lung / enzymology
-
Lung / pathology*
-
MAP Kinase Kinase 3 / metabolism
-
Mice
-
Mice, Mutant Strains
-
Pneumococcal Infections / enzymology
-
Pneumococcal Infections / pathology
-
Pneumonia, Pneumococcal / enzymology
-
Pneumonia, Pneumococcal / mortality*
-
Pneumonia, Pneumococcal / pathology*
-
Serpin E2
-
Serpins / genetics
-
Serpins / metabolism
-
Streptococcus pneumoniae / genetics
-
Streptococcus pneumoniae / pathogenicity
-
Streptolysins / genetics
-
Streptolysins / metabolism
-
Streptolysins / toxicity
-
Tumor Suppressor Proteins / genetics
-
Tumor Suppressor Proteins / physiology*
-
p38 Mitogen-Activated Protein Kinases / metabolism
Substances
-
Bacterial Proteins
-
Serpin E2
-
Serpine2 protein, mouse
-
Serpins
-
Streptolysins
-
Tumor Suppressor Proteins
-
plY protein, Streptococcus pneumoniae
-
p38 Mitogen-Activated Protein Kinases
-
MAP Kinase Kinase 3
-
CYLD protein, mouse
-
Deubiquitinating Enzyme CYLD
-
Cysteine Endopeptidases