Increased susceptibility to LPS-induced endotoxin shock in secretory leukoprotease inhibitor (SLPI)-deficient mice.
Secretory leukoprotease inhibitor (SLPI) protects tissue against the destructive action of neutrophil elastase at the site of inflammation. Recent studies on new functions of SLPI have demonstrated that SLPI may play a larger role in innate immunity than merely as a protease inhibitor. To clarify the functions of SLPI in bacterial infections, we generated SLPI-deficient mice (SLPI(-/-) mice) and analyzed their response to experimental endotoxin shock induced by lipopolysaccharide (LPS). SLPI(-/-) mice showed a higher mortality from endotoxin shock than did wild type mice. This may be explained in part by our observation that SLPI(-/-) macro-phages show higher interleukin 6 and high-mobility group (HMG)-1 production and nuclear factor kappaB activities after LPS treatment than do SLPI(+/+) macrophages. SLPI also affects B cell function. SLPI(-/-) B cells show more proliferation and IgM production after LPS treatment than SLPI(+/+) B cells. Our results suggest that SLPI attenuates excessive inflammatory responses and thus assures balanced functioning of innate immunity.
Nakamura
Akira
A
Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan.
Mori
Yuriko
Y
Hagiwara
Koichi
K
Suzuki
Takuji
T
Sakakibara
Tomohiro
T
Kikuchi
Toshiaki
T
Igarashi
Takayuki
T
Ebina
Masahito
M
Abe
Tatsuya
T
Miyazaki
Junichi
J
Takai
Toshiyuki
T
Nukiwa
Toshihiro
T
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000502:physiology; D004198:Disease Susceptibility; D024243:HMGB1 Protein / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D053481:Secretory Leukocyte Peptidase Inhibitor; D015842:Serine Proteinase Inhibitors / Q000235:genetics / Q000378:metabolism*; D012772:Shock, Septic / Q000276:immunology / Q000378:metabolism* / Q000401:mortality; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D024243:HMGB1 Protein; D020672:I-kappa B Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D009566:Nitrates; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D053481:Secretory Leukocyte Peptidase Inhibitor; D015842:Serine Proteinase Inhibitors; C506815:Slpi protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha