Transforming growth factor-β 1 blocks interleukin 4 induced cell proliferation by inhibiting a protein tyrosine phosphatase essential for signal transduction

Abstract

Transforming growth factor-β 1 (TGF-β 1) is a cytokine which exhibits pleiotropic effects on many cell types and cellular systems. TGF-β 1 has been shown to play a modulatory role in haematopoiesis and immunoregulation, expressed through its ability to inhibit the activities induced by other cytokines; however, the mechanisms underlying this activity are currently unclear. The potency of this activity varies according to the selected stimulatory cytokine and we have found that the proliferation of leukaemic cell lines induced by interleukin 4 (IL-4) is particularly sensitive to inhibition by TGF-β 1 and provides a useful model to study the mechanism of action of TGF-β. We have previously shown that IL-4 mediated mitogenic signal transduction in human systems involves the induction of phosphatase activity leading to the dephosphorylation of an 80-kDa protein (p80). We now show that TGF-β 1 inhibits IL-4 induced dephosphorylation of p80 in a dose responsive manner closely correlated with its ability to inhibit the biological activity of IL-4. This suggests that TGF-β 1 is inhibiting the same protein-tyrosine-phosphatase required by IL-4 to transduce its mitogenic signal. The biochemical mechanism underlying the biological activity of TGF-β 1 in inhibiting IL-4 bioactivity is therefore the blocking of post receptor binding signal transduction processes.