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American Journal of Pathology, Vol 143, 1713-1723, Copyright © 1993 by American Society for Investigative Pathology

REGULAR ARTICLES

Protection from tumor necrosis factor-mediated cytolysis by platelets

C Philippe, B Philippe, B Fouqueray, J Perez, M Lebret and L Baud
INSERM U.64 Hopital Tenon, France.

Infiltrating macrophages elicit tumor-destructive reactions by releasing cytolytic factors including tumor necrosis factor alpha (TNF- alpha). Because platelets represent another major component of the cell infiltrate in tumors, we examined whether they could affect TNF alpha- induced cell death. Exposure of L-929 fibrosarcoma cells to human platelets reduced TNF alpha-induced cytotoxicity and cytolysis, as determined by 51Cr release assay and DNA fragmentation assay. This inhibitory effect, which depended on the concentration of platelets (0.1 to 10 x 10(6)/0.1 ml), was as high as 50%. The decrease in responsiveness to TNF-alpha reflected neither a degradation of TNF- alpha nor an inability of L-929 cells to bind TNF-alpha. Indeed, even though Scatchard analysis indicated the presence of 100 to 150 125I-TNF- alpha binding sites/platelet with a kd of 3.8 to 6.4 nM, addition of platelets up to 5 x 10(6)/0.1 ml did not compete with 125I-TNF-alpha binding to L-929 cells. Furthermore, addition of platelets 1 or 2 hours after that of TNF-alpha was still protective suggesting that platelets rather promoted hyporesponsiveness of L-929 cells to a postbinding effect of TNF-alpha Platelet-induced reduction of TNF-alpha response could be reproduced with supernatant fluids from platelets incubated at 37 degrees C for 24 hours. The platelet-derived factor responsible for this effect was found to be a lipid of low molecular weight with high affinity for albumin and charcoal. A role for 12(S) hydroxyeicosatetraenoic acid is proposed because this metabolite reduced TNF-alpha-induced cytolysis in a dose-dependent manner, whereas other platelet-derived lipids including thromboxane A2 and platelet activating factor were inactive. These observations indicate that the role of associated platelets has to be considered when analyzing the cytotoxic and cytolytic activity of macrophage-derived TNF-alpha on tumor cells.

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