Down-regulation of the expression of cyclooxygenase-2 and prostaglandin E 2 by interleukin-4 is mediated via a reduction in the expression of prostanoid EP4 receptors in HCA-7 human colon cancer cells

• Published in: European journal of pharmacology Vol. 920; p. 174863
• Main Authors: Kitagawa, Kana, Hamaguchi, Ayaka, Fukushima, Keijo, Nakano, Yuki, Regan, John W, Mashimo, Masato, Fujino, Hiromichi
• Format: Journal Article
• Language: English
• Published: Netherlands 05-04-2022
• Subjects: Colonic Neoplasms - pathology; Cyclooxygenase 2 - metabolism; Dinoprostone - metabolism; Down-Regulation; Humans; Interleukin-4 - metabolism; Interleukin-4 - pharmacology; Prostaglandins E; Receptors, Prostaglandin E, EP2 Subtype - metabolism; Receptors, Prostaglandin E, EP4 Subtype - metabolism
• ISSN: 1879-0712
• DOI: 10.1016/j.ejphar.2022.174863

Chronic inflammatory bowel disease (IBD), which is characterized by prolonged inflammation of the gastrointestinal tract is associated with an increased risk of colorectal cancer. Recent studies revealed that the pathology of IBD is caused by hyperactivated immune responses mediated by differentiated CD4
naïve helper T cells, such as Th1 and Th17 cells, but not Th2 cells. The human E-type prostanoid 4 (EP4) receptor and its pathways have also been implicated in and/or associated with the early developmental stages of colorectal cancer along with increases in the levels of prostaglandin E
(PGE
) and cyclooxygenase-2 (COX-2), the hallmarks of colorectal carcinogenesis. In the present study, using an in silico analysis and pharmacological experiments, we demonstrated that interleukin (IL)-4, a signature cytokine of Th2 cells, down-regulated the expression of COX-2 and PGE
in the human colon cancer cell line, HCA-7. This result may be attributed to a reduction in the expression of prostanoid EP4 receptors through the induction of hypoxia inducible factor-1α via the interleukin-4 receptor-stimulated activation of signal transducer and activator of transcription 6. However, another major Th2 cytokine IL-13 had no effect on the expression of COX-2 or prostanoid EP4 receptors in HCA-7 cells. Therefore, instead of the hyperactivation of Th1/Th17 cells, the deactivation/down-regulation of Th2 cells followed by a decrease in the production of IL-4 in IBD may play a role in the cancerous transformation of cells, at least in prostanoid EP4 receptor-overactivated tumorigenesis.