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The Novel Lipopolysaccharide-Binding Protein CRISPLD2 Is a Critical Serum Protein to Regulate Endotoxin Function¹

Zhi-Qin Wang,^2* Wen-Ming Xing,^2* Hua-Hua Fan,² Ke-Sheng Wang,^* Hai-Kuo Zhang,^* Qin-Wan Wang,^* Jia Qi,^* Hong-Meng Yang,^* Jie Yang, Ya-Na Ren, Shu-Jian Cui,^* Xin Zhang,^* Feng Liu,^* Dao-Hong Lin, Wen-Hui Wang, Michael K. Hoffmann, and Ze-Guang Han^3*

*Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center, Shanghai, China; Department of Blood Engineering, Shanghai Blood Center, Shanghai, China; and Department of Pharmacology and Department of Microbiology and Immunology, New York Medical College, Valhalla, NY 10595

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 µg/ml and 290 µg/ml, respectively. Human peripheral blood granulocytes and mononuclear cells including monocytes, NK cells, and T cells spontaneously release CRISPLD2 (range, 0.2–0.9 µg/ml) and enhance CRISPLD2 secretion (range, 1.5–4.2 µg/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- 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.

³ Address correspondence and reprint requests to Dr. Ze-Guang Han, Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, 351 Guo Shou-Jing Road, Shanghai 201203, China. E-mail address: hanzg{at}chgc.sh.cn

¹ This study was supported by Chinese High-Tech Research and Development Program Grants 2006AA02Z193 and 2006AA02A305, National Natural Science Foundation for Outstanding Youth Grant 30425019, Chinese National Key Program on Basic Research Grant 2004CB518605, and the Shanghai Commission for Science and Technology.

² Z.-Q.W., W.-M.X., and H.-H.F. contributed equally to this work.