Contributions of Neisseria meningitidis LPS and non-LPS to proinflammatory cytokine response.
To determine the relative contribution of lipopolysaccharide (LPS) and non-LPS components of Neisseria meningitidis to the pathogenesis of meningococcal sepsis, this study quantitatively compared cytokine induction by isolated LPS, wild-type serogroup B meningococci (strain H44/76), and LPS-deficient mutant meningococci (strain H44/76[pLAK33]). Stimulation of human peripheral-blood mononuclear cells with wild-type and LPS-deficient meningococci showed that non-LPS components of meningococci are responsible for a substantial part of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta production and virtually all interferon (IFN)-gamma production. Based on tricine sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of LPS in proteinase K-treated lysates of N. meningitidis H44/76, a quantitative comparison was made between the cytokine-inducing capacity of isolated and purified LPS and LPS-containing meningococci. At concentrations of >10(7) bacteria/mL, intact bacteria were more potent cytokine inductors than equivalent amounts of isolated LPS, and cytokine induction by non-LPS components was additive to that by LPS. Experiments with mice showed that non-LPS components of meningococci were able to induce cytokine production and mortality. The principal conclusion is that non-LPS parts of N. meningitidis may play a role in the pathogenesis of meningococcal sepsis by inducing substantial TNF-alpha, IL-1beta, and IFN-gamma production.
Sprong
T
T
Department of Internal Medicine, University Medical Center Nijmegen, Nijmegen, The Netherlands.
Stikkelbroeck
N
N
van der Ley
P
P
Steeghs
L
L
van Alphen
L
L
Klein
N
N
Netea
M G
MG
van der Meer
J W
JW
van Deuren
M
M
D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis; D007375:Interleukin-1 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects; D008589:Meningococcal Infections / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009345:Neisseria meningitidis / Q000737:chemistry*; D018805:Sepsis / Q000209:etiology / Q000401:mortality; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D001425:Bacterial Outer Membrane Proteins; D016207:Cytokines; D018836:Inflammation Mediators; D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma