C5a receptor and thymocyte apoptosis in sepsis.
In sepsis, apoptosis occurs in many different organs. The mediators responsible for induction of apoptosis are not clearly known, although there are some suggestions that C5a and the C5a receptor (C5aR) might be directly linked to apoptosis. In the cecal ligation/puncture (CLP) model of sepsis in rats, apoptosis occurs early in a variety of organs, especially in the thymus. We demonstrate that thymocytes from normal rats show specific, saturable, and high affinity binding of 125I-labeled recombinant rat C5a. C5a binding to thymocytes was significantly increased 3 h after CLP and also when thymocytes from normal rats were first incubated in vitro with lipopolysaccharide (LPS) or IL-6. The expression of C5aR mRNA in thymocytes was markedly increased 3, 6, and 12 h after CLP and increased similarly when normal thymocytes were first exposed to LPS or IL-6 in vitro. Thymocytes obtained 2 or 3 h after CLP and exposed in vitro to C5a, but not normal thymocytes, underwent increased apoptosis, as demonstrated by annexin-V binding, coinciding with increased activation of caspases 3, 6, and 8. These data provide the first direct evidence that in the early onset of sepsis, increased expression of C5aR occurs in thymocytes, which increases their susceptibility to C5a-induced apoptosis.
Riedemann
Niels C
NC
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0602, USA.
Guo
Ren-Feng
RF
Laudes
Ines J
IJ
Keller
Katie
K
Sarma
Vidya J
VJ
Padgaonkar
Vaishalee
V
Zetoune
Firas S
FS
Ward
Peter A
PA
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001667:Binding, Competitive / Q000187:drug effects; D053148:Caspase 3; D053178:Caspase 6; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D015936:Complement C5a / Q000378:metabolism / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D015850:Interleukin-6 / Q000494:pharmacology; D007457:Iodine Radioisotopes; D008070:Lipopolysaccharides / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D018805:Sepsis / Q000503:physiopathology*; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D015703:Antigens, CD; D015850:Interleukin-6; D007457:Iodine Radioisotopes; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D011994:Recombinant Proteins; D015936:Complement C5a; C505410:Casp3 protein, rat; C505518:Casp6 protein, rat; C505528:Casp8 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053178:Caspase 6; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases