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American Journal of Pathology, Vol 137, 341-351, Copyright © 1990 by American Society for Investigative Pathology

REGULAR ARTICLES

Tumor necrosis factor alpha and lymphotoxin production in Hodgkin's disease

C Kretschmer, DB Jones, K Morrison, C Schluter, W Feist, AJ Ulmer, J Arnoldi, J Matthes, T Diamantstein and HD Flad
Forschungsinstitut Borstel, West Germany.

It is likely that the characteristic histologic features of Hodgkin's disease reflect cytokine production by the tumor cell population. Tumor necrosis factor alpha (TNF-alpha) and lymphotoxin (tumor necrosis factor beta [TNF-beta]) are important inflammatory mediators with wide- ranging effects within the lymphoreticular system. The aim of the present study was to investigate TNF-alpha and lymphotoxin production in the Hodgkin's disease-derived cell lines L428 and L540. At the product level, both cytokines could be demonstrated by immunostaining with specific monoclonal antibodies. TNF-alpha could be demonstrated by means of an enzyme-linked immunosorbent assay in culture supernatants from both cell lines as well as in cell lysates of L428 and L540 cells. Cytotoxic activity could be achieved only in L428 supernatants. This cytotoxic activity could not be blocked by the addition of a polyclonal antibody against TNF-alpha, but was partially inhibited with the monoclonal antibody against lymphotoxin. Synthesis of TNF-alpha and lymphotoxin in both L428 and L540 was confirmed by demonstrating the intracellular-specific messenger RNA (mRNA) using specific cDNA clones in Northern blot analysis. In situ hybridization studies with the TNF- alpha cDNA probe gave positive hybridization signals in L428 and in L540. These results demonstrate the transcription, translation, and export of TNF-alpha and lymphotoxin in cultured Hodgkin's disease- derived cell lines. In addition, results of preliminary experiments are presented in which we demonstrate Reed-Sternberg cells positive for TNF- alpha protein and mRNA in different Hodgkin's disease tissue biopsies, indicating that, at least for TNF-alpha, our cell line data are relevant to the neoplastic population present in Hodgkin's disease tissue.

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