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Infection and Immunity, April 2000, p. 2043-2052, Vol. 68, No. 4
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-1
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
, tumor necrosis factor alpha, and transforming growth
factor
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.
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