IL-10 production in non-small cell lung carcinoma patients is regulated by ERK, P38 and COX-2.
Bottom Line: These patients showed increased IL-10 and PGE2 with reduced IFN-γ production by ELISA.IL-10/IFN-γ levels were found to be differentially regulated via p38 and ERK mitogen-activated protein kinase (MAPK) pathways in cooperation with COX-2.The selective COX-2 inhibitor rofecoxib showed ability to alter the cytokine balance by affecting regulation of T-bet and GATA-3 transcription factors.
Affiliation: Chiplunkar Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India.Show MeSH
Related in: MedlinePlus
Mentions: To conclude, our study demonstrates that lung tumours produce high PGE2 along with other tumour-derived immunosuppressive factors in NSCLC patients. In addition to conferring the malignant and metastatic phenotype in lung cancer, PGE2 binds to EP receptors present on lymphocytes of NSCLC patients. Based on the observations we proposed a model (Fig. 8) which explores the mechanism of PGE2-mediated IL-10 production in NSCLC patients that leads to observed hyporesponsiveness in NSCLC patients. Constitutive activation of ROS due to high PGE2 levels may cause defect in TCR-ζ chain expression and inhibition of PLCγ1 leading to inhibition of intracellular calcium release resulting in reduced proliferative and activation response on TCR stimulation. Independent of TCR activation, ROS and cAMP are known to activate ERK pathway. Also constitutive activity of COX-1 and cAMP activates p38 MAPK pathway. The activation of both these pathways induces COX-2 expression and PGE2 production which stabilizes ROS and cAMP activation. Activation of ERK and p38 pathways for extended time period leads to IL-10 production which activates GATA-3 and inhibits T-bet activity resulting in impaired IFN-γ production. Production of PGE2 and IL-10 may further inhibit JNK activity which is known to be involved in IFN-γ production. Treatment of lymphocytes with NSAIDs primarily inhibits COX activity and PGE2 production; this inhibits ERK and p38 activation resulting in reduced GATA-3 and IL-10 levels which results in improved T-bet, IFN-γ and anti-tumour responses.
Affiliation: Chiplunkar Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India.