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Infection and Immunity, April 2000, p. 2043-2052, Vol. 68, No. 4
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Trehalose 6,6'-Dimycolate (Cord Factor) Enhances Neovascularization through Vascular Endothelial Growth Factor Production by Neutrophils and Macrophages

Ikuyo Sakaguchi,1,2,3,* Norikazu Ikeda,2 Miki Nakayama,2 Yoshiko Kato,2 Ikuya Yano,3 and Kenji Kaneda1

Department of Anatomy1 and Department of Bacteriology,3 Osaka City University Medical School, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, and Institute of Skin Science Club-Cosmetics Co., Ltd., 2-6-11 Nishihonmachi, Nishi-ku, Osaka 550-0005,2 Japan

Received 8 July 1999/Returned for modification 22 September 1999/Accepted 10 January 2000

Trehalose 6,6'-dimycolate (TDM) plays important roles in the development of granulomatous inflammation during infection with Mycobacterium spp., Rhodococcus spp., etc. To reveal the augmenting effect of TDM on vascular endothelial growth factor (VEGF) production and neovascularization, we investigated murine granulomatous tissue air pouches induced by Rhodococcus sp. strain 4306 TDM dissolved in Freund's incomplete adjuvant (FIA), comparing them to pouches treated with FIA alone. Histologically, granulomatous tissue and new vessel formation, which reached a maximum at day 7, was greatly enhanced by treatment with TDM. At day 1, VEGF-positive neutrophils accumulated in the pouch wall with frequency of 95% of total infiltrating cells, adhering to TDM-containing micelles. By day 3, granulomatous tissue and new vessels started to develop, and VEGF-positive macrophages appeared in a small number and gradually increased in number thereafter. The pouch contents of VEGF, interleukin-1beta , tumor necrosis factor alpha, and transforming growth factor beta  were significantly elevated in TDM-treated pouches, with peaks at days 1, 0.5, 1, and 3, respectively, compared to those of control pouches, while that of basic fibroblast growth factor showed no significant increase. Treatment with anti-VEGF antibody inhibited TDM-induced granulomatous tissue formation and neovascularization, and administration of recombinant VEGF into pouches treated with FIA alone induced neovascularization comparable to that in the TDM-treated pouches. Incubation of neutrophils and macrophages on TDM-coated plastic dishes increased the VEGF release. The present results indicate that TDM augments VEGF production by neutrophils and macrophages and induces neovascularization in the granulomatous tissue.

* Corresponding author. Mailing address: Department of Anatomy, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan. Phone: 81-6-6645-3706. Fax: 81-6-6643-3603. E-mail: ikuyos{at}clubcosmetics.co.jp.

Infection and Immunity, April 2000, p. 2043-2052, Vol. 68, No. 4
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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