Role of novel protein kinase C isoforms in Lyme arthritis.
Inflammation caused by Borrelia burgdorferi infection occurs as a result of induction of pro-inflammatory cytokines from activation of multiple signalling pathways. It has previously been shown that mitogen-activated protein kinase (MAPK) and Janus kinase/signal transducer and activator of transcription signalling pathways are activated by B. burgdorferi in cultured human chondrocytes. Protein kinase C (PKC) signalling pathways are potential candidates that may control these downstream signalling pathways. Here we show that B. burgdorferi infection leads to phosphorylation and activation of novel PKC isoforms (PKC delta, epsilon, eta and theta) in a time-dependent manner. A specific inhibitor of novel PKC isoforms blocked the induction of pro-inflammatory molecules in response to B. burgdorferi infection as did transient transfection of novel PKC dominant-negative plasmids into chondrocytes. B. burgdorferi-induced p38 MAPK phosphorylation was also significantly inhibited by an inhibitor of novel PKC isoforms, suggesting that PKC activation occurs upstream of p38 activation. In vivo, administration of an inhibitor of classical and novel PKC isoforms to C3H/HeN mice infected with B. burgdorferi resulted in significantly reduced ankle inflammation and swelling. In conclusion, these data suggest that novel PKC isoforms are specifically activated by B. burgdorferi infection and this can contribute to the regulation of inflammation in vitro and in vivo.
Shin
Ok S
OS
Tufts New England Medical Center, Tufts University School of Medicine, Tupper Research Institute, Division of Geographic Medicine and Infectious Diseases, Boston, MA 02111, USA.
Behera
Aruna K
AK
Bronson
Roderick T
RT
Hu
Linden T
LT
D000818:Animals; D000842:Ankle / Q000473:pathology; D025065:Borrelia burgdorferi / Q000502:physiology*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000201:enzymology; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D008193:Lyme Disease / Q000201:enzymology* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D007527:Isoenzymes; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases