The role of parallel signaling pathways in maintaining lymphoid cell survival

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2007-06-13T15:53:43Z
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T lymphocytes are critical for a functional immune system. However, their uncontrolled activation and growth can be manifested as a number of lymphoid derived diseases such as autoimmunity, allograft rejection, and lymphoma. Therefore, understanding the role of key signaling molecules and the ability to modify their activity in mature cells may provide new therapeutic strategies to treat T cell mediated disorders. The purpose of this study was to dissect the role of key signaling pathways activated by interleukin-2 (IL2) and other T cell growth factors that share the IL2 receptor gamma chain (γc) (IL2, 4, 7, 9, 13, 15, 21) in mediating T cell growth and survival. To accomplish this objective, antisense oligonucleotides targeted against signaling molecules including γc, Raf isoforms, Stat3, traditional pharmaceuticals to disrupt Janus tyrosine kinase 3, PI3K (wortmannin), mTor (rapamycin) and MEK kinase (PD98059) activity were utilized and their effects characterized in lymphoid cells. Antisense oligonucleotide targeted against γc inhibited protein expression (40%) in a lymphoid tumor cell line inducing apoptotic death and cell cycle arrest in G2-M phase, as measured by FACS analysis of Annexin V and Propidium Iodide stained cells. Inhibition of Jak3 (PNU156804) showed similar effects and disrupted Stat5 and MAPK activation. Novel evidence is shown here that IL2 can activate multiple isoforms of Raf, and inhibition of these isoforms by antisense oligonucleotides failed to affect cell survival or Stat5 activation. Similar results were found for inhibition of PI3K, mTor and MEK kinases. Lastly, we show that Stat3 antisense oligonucleotide treatment of a human tumor cell line bearing constitutively activated Stat3 induces cell death (40%, measured with TUNEL assay) but that IL2 can rescue these cells possibly mediated via Stat5 that becomes hyperactivated in Stat3 deleted cells. Evidence is provided that suggests Bcl2 plays key role in this cell survival process. We conclude from our findings that the Mapk, Stat and PI3K pathways likely function as separate entities in lymphoid cells, suggesting that evolutionarily these pathways might have evolved to perform specialized cell functions that may be redundant for other T cell activities. Moreover, our results suggest that Stat molecules are critical to the survival and growth of T cells and represent a therapeutically relevant target to combat T cell derived disorders.

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