Intracerebral HIV glycoprotein (gp120) enhances tumor metastasis via centrally released interleukin-1.
Infection with the human immunodeficiency virus (HIV) is associated with a high incidence of cancers. This relationship does not appear to be due to a direct effect of the virus, and may be mediated by neuroimmune interactions since the HIV glycoprotein, gp120, enters the brain soon after infection with HIV, and intracerebroventricular (i.c.v.) infusion of gp120 suppresses aspects of cellular and tumor immunity. It has been speculated that this suppression may be attributed to the release of interleukin-1 (IL-1) in the brain induced by gp120. Using an in vivo tumor model, we examined the effect of centrally administered gp120 on tumor metastasis and lung clearance of mammary adenocarcinoma (MADB106) tumor cells in rats, and the role played by brain IL-1 in mediating these effects. We demonstrate that central administration of gp120 (4 microg) significantly (p<0.05) increased the retention of tumor cells in the lungs and significantly (p<0.02) enhanced the development of tumor metastases. Central administration of IL-1beta (10 ng) also significantly (p<0.05) increased retention of tumor cells in the lungs. The effect of gp120 on lung retention of tumor cells was blocked by co-administration of alpha-melanocyte stimulating hormone (alpha-MSH, 20 ng), a hormone that blocks many of the biological effects of IL-1, or the IL-1 receptor antagonist (50 microg). Given that systemic administration of gp120 or IL-1beta had no effect on the retention of tumor cells in the lungs, these findings indicate that gp120-induced secretion of IL-1 within the brain most likely mediates the effects of gp120 on tumor metastasis. These findings suggest a possible neuroimmune mechanism to account for the increased incidence and aggressiveness of tumors in HIV-infected patients.
Hodgson
D M
DM
Dept. of Neurobiology and Brain Research Institute, School of Medicine, University of California, Los Angeles, CA 90095, USA. hodgson@psych.ucla.edu
Yirmiya
R
R
Chiappelli
F
F
Taylor
A N
AN
D000230:Adenocarcinoma / Q000556:secondary*; D000704:Analysis of Variance; D000818:Animals; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D007276:Injections, Intraventricular; D007375:Interleukin-1 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000556:secondary*; D008297:Male; D008657:Metabolic Clearance Rate; D051381:Rats; D011916:Rats, Inbred F344; D014407:Tumor Cells, Cultured; D000521:alpha-MSH / Q000494:pharmacology
D015699:HIV Envelope Protein gp120; D007375:Interleukin-1; D000521:alpha-MSH