Transforming Growth Factor-b, Regulatory functions on normal lymphocytes and tumor outgrowth Regulatory functions on normal lymphocytes and tumor outgrowth

Sammanfattning: Transforming growth factor-beta (TGF-b) is a well-characterised growth regulatory factor, which acts on most cell types. This thesis has focused on the regulatory roles of TGF-b on normal lymphocytes. One interesting finding is that TGF-b acts both costimulatory and inhibitory on T-lymphocytes. The costimulatory effect depends on the presence of monocytes and is mediated by these cells. Furthermore, we have found that TGF-b costimulates T-lymphocytes at an early activation phase but inhibits them at a late activating phase. The costimulatory effect of TGF-b results in an increased viability of T-cells and a decrease in the amount of apoptotic cells. When acting costimulatory, TGF-b also induces a shift towards a Th2 cytokine profile with an increased production of IL-10 and a decreased production of IFN-g. This latter finding is crusial for TGF-b-induced costimulation of T-lymphocytes. We also show that TGF-b, when acting costimulatory, down-regulates phosphorylation and activation of ERK. Furthermore, we have found that the MEK-1 inhibitor, known to block phosphorylation of ERK, like TGF-b acts costimulatory on T-lymphocytes. In addition we also demonstrate that the MEK-1 inhibitors and TGF-b decrease the production of IFN-g. The local effect of TGF-b1 on tumor outgrowth have been investigated. By transfecting a colon carcinoma, which lacked detectable levels of TGF-b1, we demonstrate that the induction of TGF-b1 secretion results in a slower tumor outgrowth compared to the control tumor transfected with vector only. An increased infiltration of T-lymphocytes, granulocytes and macrophages into the tumor area was seen. Lymphocytes from the TGF-b-transfected tumor secreted large amounts of both IL-10 and TNF-a compared to the lymphocytes from the vector control tumor.