The novel lipopolysaccharide-binding protein CRISPLD2 is a critical serum protein to regulate endotoxin function.
LPS is an immunostimulatory component of Gram-negative bacteria. Acting on the immune system in a systemic fashion, LPS exposes the body to the hazard of septic shock. In this study we report that cysteine-rich secretory protein LCCL domain containing 2 (CRISPLD2/Crispld2; human and mouse/rat versions, respectively), expressed by multitissues and leukocytes, is a novel LPS-binding protein. As a serum protein, median CRISPLD2 concentrations in health volunteers and umbilical cord blood samples are 607 microg/ml and 290 microg/ml, respectively. Human peripheral blood granulocytes and mononuclear cells including monocytes, NK cells, and T cells spontaneously release CRISPLD2 (range, 0.2-0.9 microg/ml) and enhance CRISPLD2 secretion (range, 1.5-4.2 microg/ml) in response to stimulation of both LPS and humanized anti-human TLR4-IgA Ab in vitro. CRISPLD2 exhibits significant LPS binding affinity similar to that of soluble CD14, prevents LPS binding to target cells, reduces LPS-induced TNF-alpha and IL-6 production, and protects mice against endotoxin shock. In in vivo experiments, serum Crispld2 concentrations increased in response to a nontoxic dose of LPS and correlated negatively with LPS lethality, suggesting that CRISPLD2 serum concentrations not only are indicators of the degree of a body's exposure to LPS but also reflect an individual's LPS sensitivity.
Wang
Zhi-Qin
ZQ
Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center, Shanghai, China.
Xing
Wen-Ming
WM
Fan
Hua-Hua
HH
Wang
Ke-Sheng
KS
Zhang
Hai-Kuo
HK
Wang
Qin-Wan
QW
Qi
Jia
J
Yang
Hong-Meng
HM
Yang
Jie
J
Ren
Ya-Na
YN
Cui
Shu-Jian
SJ
Zhang
Xin
X
Liu
Feng
F
Lin
Dao-Hong
DH
Wang
Wen-Hui
WH
Hoffmann
Michael K
MK
Han
Ze-Guang
ZG
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000097:blood / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006098:Granulocytes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D050835:Interferon Regulatory Factors / Q000097:blood / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000276:immunology* / Q000494:pharmacology; D012772:Shock, Septic / Q000276:immunology* / Q000517:prevention & control; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; C525599:CRISPLD2 protein, human; D015815:Cell Adhesion Molecules; D007155:Immunologic Factors; D050835:Interferon Regulatory Factors; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha