| Poor prognosis in Non Small Cell Lung Carcinoma (NSCLC) patients correlates with elevated Interleukin-10 (IL-10) serum levels. Elevated IL-10 serum levels can indicate an increased rate of recurrent tumors and metastases, decreased responsiveness to chemotherapy and radiation, and decreased survival time. IL-10 can act directly as an autocrine factor that could alter immunogenicity, expression of angiogenic factors and matrix metalloproteases, proliferation, or cell survival. These studies focused on the direct effects of IL-10 on lung tumor cells using murine adenocarcinoma cell lines: Lewis Lung (LL2) Line 1 Neo, MLE-12 MLE-15, and squamous cell line: KLN 205. Studies demonstrated the presence of both IL-10 receptor chains on all cell lines, with none of the cell lines producing IL-10 endogenously. The IL-10 signaling pathway was considered functional by the up-regulation of Suppressor of Cytokine Signaling 3 (SOCS3) message expression in response to exogenous IL-10. IL-10 modified the MHC I and II message in all five cell lines, but did not modify protein expression. Vascular Endothelial Growth Factor (VEGF), Angiopoieten 1, and Angiopoieten 2 message expression were altered by IL-10 in a cell line and cell density dependent manner. IL-10 did not affect proliferation or cell cycle. However, IL-10 enhanced the general viability of the tumor cells and promoted resistance to apoptosis in all cell lines. IL-10 pretreatment of LL2 cells resulted in the delayed movement into early and late apoptosis when cells were subjected to ionizing irradiation, UV-C irradiation, or cisplatin. Cytotoxic T cell mediated lysis of LL2 cells was decreased significantly following IL-10 pretreatment of the tumor cells. IL-10 increased Akt phosphorylation, NFkappaB activation, STAT3 tyrosine phosphorylation; and decreased Jnk phosphorylation and caspase 3 cleavage in LL2 cells. The Janus kinase (JAK1) inhibitor, JSI-124, induced apoptosis in cells, but was abrogated by IL-10 pretreatment. This observation suggests that IL-10 mediates apoptosis resistance through a pathway that is independent of STAT3 tyrosine phosphorylation. These results suggest that a primary effect of IL-10 on lung tumor cells may be increased cell survival in the face of chemo/radiotherapy or cytotoxic T cell attack, resulting in poorer prognosis for NSCLC patients.; Keywords: Intedeukin-10, JSI-124, Lung Cancer, STAT3, Apoptosis. |
