Downregulation of IL-6-induced STAT3 tyrosine phosphorylation by TGF-β1 is mediated by caspase-dependent and -independent processes

A.T.J. Wierenga, J.J. Schuringa, B.J.L. Eggen, W. Kruijer, E. Vellenga

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18 Citations (Scopus)

Abstract

To explore the possible cross-talk between the IL-6 and TGF-β1 pathways in AML blast cells, the effect of TGF-β1 pretreatment on IL-6-induced STAT3 tyrosine phosphorylation was studied. A reduction of STAT3 tyrosine phosphorylation after TGF-β1 pretreatment was observed in four out of 40 AML cases (10%), although all of the AML cases responded to TGF-β1 by means of SMAD3 translocation. The reduced IL-6-mediated STAT3 tyrosine phosphorylation after pre-treatment with TGF-β1 was associated with apoptosis and coincided with the degradation of certain cellular proteins, including JAK1 and -2 and Tyk2, without affecting the ERK expression and phosphorylation. Furthermore, treatment of AML blasts with the cytostatic agent VP16, as an alternative way to induce apoptosis, resulted in a similar degree of degradation of JAK kinases and concomitant reduction of IL-6-mediated STAT3 tyrosine phosphorylation. Although degradation of JAK kinases could be rescued by incubating the cells with the pancaspase inhibitor Z-VAD-fmk, the attenuating effect of TGF-β1 treatment on the STAT3 tyrosine phosphorylation was still partly present. It was shown that in AML cells cultured in the presence of Z-VAD-fmk, TGF-β1 pretreatment resulted in a reduction of JAK1 phosphorylation upon IL-6 stimulation. Expression of SOCS1 and -3 could be ruled out as a possible cause of reduced JAK1 phosphorylation levels in the investigated AML case.
Original languageEnglish
Pages (from-to)675-682
Number of pages8
JournalLeukemia
Volume16
Issue number4
DOIs
Publication statusPublished - Apr-2002

Keywords

  • caspases
  • apoptosis
  • TGF-β1
  • IL-6
  • STAT3

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