Endotoxin binding protein : Novel therapeutic strategy of endotoxin shock.
| Project/Area Number |
08670314
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Bacteriology (including Mycology)
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| Research Institution | Iwate Medical University |
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Principal Investigator |
HIRATA Michimasa Iwate Medical University, Department of Bacteriology, Associate professor., 医学部, 助教授 (20048359)
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| Project Period (FY) |
1996 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 1997: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1996: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | Lipopolysaccharide(LPS) / Endotoxin-binding protein / Endotoxinneutralization / Synthetic peptides / Antibacterial peptide / Innate immunity / Host defense mechanism / 生体防御 |
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| Research Abstract |
We purified 18kDa cationic anti-microbial protein (CAP18) with lipopolysaccharide (LPS)-neutralizing activities from rabbit granulocytes. We also cloned a CAP18 family protein from a human bone marrow library. The cloned DNA encoded 140 amino acid residues (CAP181-140). Like the rabbit protein this molecule is comprised of two domains, a highly conserved N-terminal domain of unknown function and a less conserved C-terminal anti-microbial and LPS-neutralizing domain. In the present study, we synthesized new human peptides to identify in more detail the active domain within C-terminal fragment. Synthetic peptide (27 mer, F12-V38) of C-terminal fragment binds to LPS,inhibits LPS-induced activation of Limulus amebocyte lysate, LPS-induced reactive nitrogen release by macrophages and protect mice from LPS lethality. Treatment with the 27 mer peptide also blocked the increase in TNF-alpha levels induced by LPS injection. this peptide also showed antimicrobial activity versus both gram-negative bacteria such as Escerichia coli O157 : H7, salmonella typhimiurium, Klebsiella pneumoniae, Pseudomonas aeruginosa and gram-positive bacteria such as Staphylo-coccus aureus and Streptococcus pneumoniae. Truncation of hydrophobic amino acids from this 27 mer peptide caused a significant decrease in all activities indicating that this 27-mer fragment is the minimal antimicrobial and LPS-neutralizing domain of CAP18.
The amphipathic and alpha-helical structure of this peptide may play a major role in the expression of these activities. The importance of C-terminus hydophobic residues in CAP18 was also suggested. CAP18 and derived peptides may act as host defense protein against infectious diseases, and have therapeutic potential for sepsis and endotoxin shock.
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Report
(3 results)
Research Products
(26 results)
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[Publications] Agarwala, K.L., KAwabata, S., Hirata, M., Miyagi, M., Tsunasawa, S., Iwanaga, S.: "A cysteine protease inhibitor stored in the large granules of horseshoe crab hemocytes : Purification, characterization, cDNA cloning and tissue localization" J.Biochem.119(1). 85-94 (1996)
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[Publications] Kawabata, S., Nagayama, R., Hirata, M., Shigenaga, T., Agarwala, K.L., Saito, T., Cho, J., Nakajima, T., Takagi, T., and Iwanaga, S.: "Tachycitin, a small granular component in horseshoe crab hemocytes, is an antimicrobial protein with chitin-binding activity." J.Biochem.120(6). 1253-1260 (1996)
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[Publications] Kawabata, S., Tokunaga, F., Kugi, Y., Motoyama, S., Miura, Y., Hirata, M., Iwanaga, S.: "Limulus factor D,a43-kDa protein isolated from horseshoe crab hemocytes, is a serine protease homologue with antimicrobial activity." FEBS Letter.398. 146-150 (1996)
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[Publications] Kirikae, T., Hirata, M., Yamasu, H., Kirikae, F., Tamura, H., Kayama, F., Nakatsuka, K.and Nakano, M.: "Protective effects of a human CAP18-derived peptide against murine endotoxemia." Infect. Immun.(in press). (1998)
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[Publications] Larrick, J.W., Hirata, M., Balint, R.F., Huang, T., Chen, C., Zhong, J and Wright, S.C.: CAP18 : A novel LPS-binding/antimicrobial protein. Novel therapeutic strategies in the treatment of sepsis. Edited by Morrison, D.C and Ryan, J.L.71-91. Marcel Dekker, Inc., (1996)
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[Publications] Hirata, M., Wright, S.C., Larrick, J.W: Elsevier Science B.V., (1996)Endotoxin-neutralizing proteins for sepsis and endotoxin shock. Shock, from molecular and cellular level to whole body. Edited by okada, K., Ogata, H., 109-115.
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