Protective effects of IL-6 blockade in sepsis are linked to reduced C5a receptor expression.
IL-6 is known to be an important pro- and anti-inflammatory cytokine, which is up-regulated during sepsis. Our previous work has suggested a role for IL-6 in the up-regulation of C5aR in sepsis. We reported earlier that interception of C5a or C5aR results in improved outcomes in experimental sepsis. Using the cecal ligation/puncture (CLP) model in mice, we now demonstrate that treatment with anti-IL-6 Ab (anti-IL-6) results in significantly improved survival, dependent on the amount of Ab infused. CLP animals showed significantly increased binding of 125I-labeled anti-C5aR to organs when compared to either control mice at 0 h or CLP animals infused with normal rabbit 125I-labeled IgG. Binding of 125I-labeled anti-C5aR to lung, liver, kidney, and heart was significantly decreased in anti-IL-6-treated animals 6 h after CLP. RT-PCR experiments with mRNA isolated from various organs obtained 3, 6, and 12 h after CLP demonstrated increased C5aR mRNA expression during the onset of sepsis, which was greatly suppressed in CLP mice treated with anti-IL-6. These data suggest that IL-6 plays an important role in the increased expression of C5aR in lung, liver, kidney, and heart during the development of sepsis in mice and that interception of IL-6 leads to reduced expression of C5aR and improved survival.
Riedemann
Niels C
NC
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-0602, USA.
Neff
Thomas A
TA
Guo
Ren-Feng
RF
Bernacki
Kurt D
KD
Laudes
Ines J
IJ
Sarma
J Vidya
JV
Lambris
John D
JD
Ward
Peter A
PA
D000595:Amino Acid Sequence; D000818:Animals; D019138:Antibodies, Blocking / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D001666:Binding Sites, Antibody; D002432:Cecum; D015936:Complement C5a / Q000378:metabolism*; D015536:Down-Regulation / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology; D007668:Kidney / Q000276:immunology / Q000378:metabolism; D008026:Ligation; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009206:Myocardium / Q000276:immunology / Q000378:metabolism; D011677:Punctures; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D018805:Sepsis / Q000276:immunology* / Q000401:mortality / Q000628:therapy*; D016019:Survival Analysis; D000093242:Interleukin-6 Inhibitors
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015936:Complement C5a; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D012333:RNA, Messenger; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D000093242:Interleukin-6 Inhibitors