Interleukin 1 (IL-1) production is not essential for acquired resistance of human A375 melanoma cells to anti-proliferative effect of IL-1

Abstract

The proliferation of human melanoma cell line A375-6 is inhibited by interleukin I (IL-I). However, the cells acquired resistance to IL-I after a long period of culture. We have reported that 2 resistant subclones, A375-R8 and -R19, produced IL-la constitutively and that IL-I induced IL-6 production in an autocrine manner. Therefore, we supposed that IL-la production renders the cells resistant to IL-I. To investigate the relationship between IL-la production and IL-I resistance, we transfected the IL-I a expression plasmid to the IL-I -sensitive clone, A375-6, and the anti-sense mRNA expression plasmid to IL-I-resistant cells, A375-R8 and -R19. A375-6MS, a transfectant of mature IL-la expression plasmid, expressed IL-la mRNA and produced IL-I activity at a level comparable to the resistant cells. The transfectant also produced IL-6 and exhibited augmented expression of Mn-SOD mRNA. However, IL-I sensitivity of this transfectant was not affected. With respect to sensitivity to anti-proliferative effects of other cytokines, such as IL-6 and TNFa, there was no difference between the transfectant and parent cells. Although A375-R8PH I 0 and -R19PH 10, transfectants of IL-la anti-sense mRNA expression plasmid, exhibited a decrease in the level of IL-l production, their IL-I sensitivity did not differ from parent cells. These results, therefore, suggest that IL-la production is not essential or suffkient for the acquisition of resistance to the antiproliferative effect of IL-I.o 1996 Wilq-Liss, Inc.IL-1 is a multifunctional cytokine that regulates immunoreaction, inflammation, hematopoiesis and homeostasis (Dinarello, 1994). IL-1 also regulates the proliferation of various cell types in both positive and negative manners. Thymocytes, B cells and fibroblasts are representatives that proliferate in response to I G 1 (Gery et al., 1972; Freedman et al., 1988;Schmidt et al., 1982). However, the proliferation of many cell types, including several human mammary tumor cell lines, the murine myeioid leukemic cell line (Ml) and human endothelial cells, is inhibited by IL-1 (Gaffney and Tsai, 1986;Onozaki et al., 1987; Maier et al., 1990).The human melanoma cell line A375-6 is the first found to be inhibited of its proliferation by IL-1 (Onozaki et al., 1985). We have noticed that A375-6 cells became resistant to IL-1 after a long period of culture. Two IL-1-resistant subclones, A375-RB and -R19, were obtained, and their characteristics have been studied. These 2 subclones expressed functional IL-1 receptor regardless of their resistance to IL-1 and produced IL-la constitutively. They also produced IL-6 constitutively, and the production was shown to result from the autocrine effect of endogenous IL-la. The cells also became resistant to the anti-proliferative effect of IL-6 (Araki et at., 1994).The progression of human melanoma has been extensively studied. In an early stage (the radial growth phase), the growth of melanoma cells depends on several growth factors and can be inhibited by several cytokines, such as transforming...

P2X7/PANX1 as a new target for melanoma?

“…First, secretion of IL-1β, which under normal conditions is strictly regulated, becomes constitutive in some melanoma cells [3,4]. Second, melanoma cells can acquire resistance to the direct anti-proliferative/cytotoxic effects of this cytokine [5,6].Further advancement in this area was recently reported by Okammoto and Fujita who correlated melanoma aggressiveness to constitutive IL-1β secretion [2]. Their work showed that loss of inflammasome regulation and autonomous IL-1β secretion was limited to advanced but not early-stage melanoma cells.…”