Critical role of the complement system in group B streptococcus-induced tumor necrosis factor alpha release.
Group B Streptococcus (GBS) is a major cause of newborn sepsis and meningitis and induces systemic release of tumor necrosis factor alpha (TNF-alpha), believed to play a role in morbidity and mortality. While previous studies have shown that GBS can induce TNF-alpha release from monocytes and macrophages, little is known about the potential modulating effect of plasma or serum on GBS-induced TNF-alpha release, and there are conflicting reports as to the host receptors involved. In a human whole-blood assay system, GBS type III COH-1 potently induced substantial monocyte TNF-alpha release in adult peripheral blood and, due to a higher concentration of monocytes, 10-fold-greater TNF-alpha release in newborn cord blood. Remarkably, GBS-induced TNF-alpha release from human monocytes was enhanced approximately 1000-fold by heat-labile serum components. Experiments employing C2-, C3-, or C7-depleted serum demonstrated that C3 activation via the alternative pathway is crucial for potent GBS-induced TNF-alpha release. Accordingly, whole blood from C3-deficient mice demonstrated significantly reduced GBS-induced TNF-alpha release. Preincubation with human serum enhanced the TNF-alpha-inducing activity of GBS in a C3- and factor B-dependent manner, implying deposition of complement components via the alternative pathway. GBS-induced TNF-alpha release was inhibited by monoclonal antibodies directed against each of the components of CR3 and CR4: the common integrin beta subunit CD18 and the alpha subunits CD11b (of CR3) and CD11c (of CR4). Blood derived from CR3 (CD11b/CD18)-deficient mice demonstrated a markedly diminished TNF-alpha response to GBS. We conclude that the ability of plasma and serum to greatly amplify GBS-induced TNF-alpha release reflects the activity of the alternative complement pathway that deposits fragments on GBS and thereby enhances CR3- and CR4-mediated monocyte activation.
Levy
Ofer
O
Division of Infectious Diseases, Children's Hospital, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. olevy@rics.bwh.harvard.edu
Jean-Jacques
Rochelle M
RM
Cywes
Colette
C
Sisson
Richard B
RB
Zarember
Kol A
KA
Godowski
Paul J
PJ
Christianson
Jennifer L
JL
Guttormsen
Hilde-Kari
HK
Carroll
Michael C
MC
Nicholson-Weller
Anne
A
Wessels
Michael R
MR
D000328:Adult; D000818:Animals; D003176:Complement C3 / Q000502:physiology; D011415:Complement Factor B / Q000502:physiology; D003165:Complement System Proteins / Q000502:physiology*; D006801:Humans; D016167:Integrin alphaXbeta2; D018950:Lipopolysaccharide Receptors / Q000502:physiology; D016177:Macrophage-1 Antigen; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism; D044967:Serum / Q000502:physiology; D013292:Streptococcus agalactiae / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D003176:Complement C3; D016167:Integrin alphaXbeta2; D018950:Lipopolysaccharide Receptors; D016177:Macrophage-1 Antigen; D014409:Tumor Necrosis Factor-alpha; D003165:Complement System Proteins; D011415:Complement Factor B