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Clinical and Diagnostic Laboratory Immunology, May 2004, p. 483-495, Vol. 11, No. 3
1071-412X/04/$08.00+0     DOI: 10.1128/CDLI.11.3.483-495.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Toll-Like Receptor 4 Mediates the Antitumor Host Response Induced by a 55-Kilodalton Protein Isolated from Aeginetia indica L., a Parasitic Plant

Masato Okamoto,^1* Go Oh-e,¹ Tetsuya Oshikawa,¹ Sachiko Furuichi,¹ Tomoyuki Tano,¹ Sharif U. Ahmed,¹ Sachiko Akashi,² Kensuke Miyake,² Osamu Takeuchi,³ Shizuo Akira,³ Kunisuke Himeno,⁴ Mitsunobu Sato,¹ and Shinya Ohkubo⁵

Second Department of Oral and Maxillofacial Surgery, The University of Tokushima School of Dentistry,¹ Ohkubo Hospital, Tokushima,⁵ Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Tokyo,² Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka,³ Department of Microbiology and Immunology, Kyushu University School of Medicine, Fukuoka, Japan⁴

Received 5 June 2003/ Returned for modification 29 December 2003/ Accepted 18 February 2004

A 55-kDa protein named AILb-A, isolated from the seed extract of Aeginetia indica L., a parasitic plant, induces a Th1-type T-cell response and elicits a marked antitumor effect in tumor-bearing mice. In the present study, we examined the role of Toll-like receptors (TLRs), which have been implicated in pathogen-induced cell signaling, in AILb-A-induced immune responses. In the luciferase assay using a nuclear factor (NF)-B-dependent reporter plasmid, AILb-A induced NF-B activation in the cells transfected with TLR4, but not with those transfected with the TLR2 gene, in a dose-dependent manner. TLR4-mediated NF-B activation induced by AILb-A but not by lipopolysaccharide (LPS) was also observed under serum-free conditions. In in vitro experiments using human peripheral blood mononuclear cells, AILb-A-induced cytokine production was markedly inhibited by anti-TLR4 but not by anti-CD14 antibody, while LPS-induced, TLR4-mediated cytokine production was inhibited by anti-CD14 as well as anti-TLR4 antibodies. Cytokine production, killer cell activities, maturation of dendritic cells, phosphorylation of mitogen-activated protein kinases, and nuclear translocation of interferon-regulatory factor 3 induced by AILb-A were severely impaired in TLR4-deficient but not TLR2-deficient mice. Transfection of TLR4-deficient mouse-derived macrophages with the TLR4 expression plasmid led AILb-A to induce cytokines. Finally, the antitumor effect of AILb-A was also impaired in TLR4-deficient and TLR4-mutated mice. These findings suggest that TLR4 mediates antitumor immunity induced by the plant-derived protein AILb-A.

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* Corresponding author. Mailing address: Second Department of Oral and Maxillofacial Surgery, The University of Tokushima School of Dentistry, 3-18-15 Kuramoto-cho, Tokushima 7708504, Japan. Phone: 81 88 633 7354. Fax: 81 88 633 7462. E-mail: mokamoto{at}dent.tokushima-u.ac.jp.

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Clinical and Diagnostic Laboratory Immunology, May 2004, p. 483-495, Vol. 11, No. 3
1071-412X/04/$08.00+0     DOI: 10.1128/CDLI.11.3.483-495.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.