ALTERATIONS IN TNF-ALPHA SIGNAL-TRANSDUCTION IN RESISTANT HUMAN PAPILLARY THYROID-CARCINOMA CELLS

Tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamm a) inhibit the growth of the human papillary thyroid carcinoma (PTC) c ell line, NP. Exposure of NP cells to TNF-alpha resulted in the develo pment of several PTC cell lines (R30, R45, and R60) with graded loss t o the TNF-alpha-induced antiproliferation, termed resistance. In contr ast, the NP cells and the resistant cells were equally sensitive to th e antiproliferative action of interferon-gamma. Utilizing TNF-alpha re ceptor-specific agonist monoclonal antibodies, we demonstrated that th e TNF-alpha receptor p55 mediated the antiproliferative action of TNF- alpha, while the p75 receptor did not affect cell proliferation in the NP cell line. The resistant PTC cell lines, however, showed a graded loss of p55 receptor-mediated antiproliferation and a concomitant acti vation of a p75 receptor-mediated growth stimulation. Shedding of TNF receptors is an important mechanism of TNF-alpha receptor metabolism. The p55 receptor mediated the TNF-alpha-induced up-regulation of the s hedding of the p75 TNF-alpha receptor. The p75 receptor mediated the T NF-alpha-induced down-regulation of the shedding of the p55 receptor. However, the shedding of the p75 receptor was decreased and the sheddi ng of the p55 receptor was increased in the resistant R60 cell line co mpared with the NP cell line, in the presence and absence of TNF-alpha . In contrast, IFN-gamma increased shedding of both p55 and p75 TNF-al pha receptors in NP and R60 cell lines with equal potency. Furthermore , the resistant PTC cell lines have increased basal manganous superoxi de dismutase (MnSOD) expression and blunted induction of MnSOD mRNA up on short-term TNF-alpha treatment (less than 2 h of treatment). The re sults indicate that a decrease in signal transduction via the p55 TNF- alpha receptor and concomitant increase in signal transduction via the p75 TNF-alpha receptor are involved in the development of MTC cell re sistance.