R-roscovitine reduces lung inflammation induced by lipoteichoic acid and Streptococcus pneumoniae.
Bacterial pneumonia remains associated with high morbidity and mortality. The gram-positive pathogen Streptococcus pneumoniae is the most common cause of community-acquired pneumonia. Lipoteichoic acid (LTA) is an important proinflammatory component of the gram-positive bacterial cell wall. R-roscovitine, a purine analog, is a potent cyclin-dependent kinase (CDK)-1, -2, -5 and -7 inhibitor that has the ability to inhibit the cell cycle and to induce polymorphonuclear cell (PMN) apoptosis. We sought to investigate the effect of R-roscovitine on LTA-induced activation of cell lines with relevance for lung inflammation in vitro and on lung inflammation elicited by either LTA or viable S. pneumoniae in vivo. In vitro R-roscovitine enhanced apoptosis in PMNs and reduced tumor necrosis factor (TNF)-α and keratinocyte chemoattractant (KC) production in MH-S (alveolar macrophage) and MLE-12/MLE-15 (respiratory epithelial) cell lines. In vivo R-roscovitine treatment reduced PMN numbers in bronchoalveolar lavage fluid during LTA-induced lung inflammation; this effect was reversed by inhibiting apoptosis. Postponed treatment with R-roscovitine (24 and 72 h) diminished PMN numbers in lung tissue during gram-positive pneumonia; this step was associated with a transient increase in pulmonary bacterial loads. R-roscovitine inhibits proinflammatory responses induced by the gram-positive stimuli LTA and S. pneumoniae. R-roscovitine reduces PMN numbers in lungs upon LTA administration by enhancing apoptosis. The reduction in PMN numbers caused by R-roscovitine during S. pneumoniae pneumonia may hamper antibacterial defense.
Center for Infection and Immunity, Amsterdam, the Netherlands. a.j.hoogendijk@amc.uva.nl
Arie J
AJ
Hoogendijk
Joris J T H
JJ
Roelofs
Janwillem
J
Duitman
Miriam H P
MH
van Lieshout
Dana C
DC
Blok
Tom
T
van der Poll
Catharina W
CW
Wieland
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007958:Leukocyte Count; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D011014:Pneumonia / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000382:microbiology; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use*; D000077546:Roscovitine; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000502:physiology*; D013682:Teichoic Acids
D000590:Amino Acid Chloromethyl Ketones; D018925:Chemokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D011687:Purines; D013682:Teichoic Acids; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D000077546:Roscovitine; C009900:lipoteichoic acid; D018844:Cyclin-Dependent Kinases; D053148:Caspase 3