Il-4 up-regulates cyclooxygenase-1 expression in macrophages

Authors: SHAY, ASHLEY - Pennsylvania State University; TUKARAMRAO, DIWAKAR - Pennsylvania State University; GUAN, BO-JHIH - Pennsylvania State University; NARAYAN, VIVEK - Pennsylvania State University; Urban, Joseph; PRABHU, SANDEEP - Pennsylvania State University

Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/6/2017
Publication Date: 9/1/2017
Citation: Shay, A.E., Tukaramrao, D.B., Guan, B., Narayan, V., Urban Jr, J.F., Prabhu, S.K. 2017. Il-4 up-regulates cyclooxygenase-1 expression in macrophages. Journal of Biological Chemistry. 292(35):14544-14555. https://doi.org/10.1074/jbc.M117.785014.
DOI: https://doi.org/10.1074/jbc.M117.785014

Interpretive Summary: Worm parasites can infect humans and animals and stimulate production of a class of protein mediators called Th2 cytokines that facilitate the expulsion of parasites from the intestine but have also been shown to reduce inflammation and assist in tissue repair mechanisms. The current study, conducted by scientists at Pennsylvania State University and the U.S. Department of Agriculture's Agricultural Research Service in Beltsville, Maryland, showed that a macrophage cell type polarized to become alternatively activated by the Th2 cytokines also produces potent pro-resolving mediators, such as prostaglandin D2 metabolites produced by the cyclooxygenase (Cox) pathway. The study further showed that Cox-1 in particular was induced by the Th2 cytokines in alternatively activated macrophages. Blocking of Cox-1 production exacerbates tissue injury during allergic responses in the lungs suggesting that it may play a role in an anti-inflammatory response in that tissue. These studies suggest a novel paradigm where parasite-induced Th2 cytokines regulate Cox-1 production to play a key role in tissue homeostasis and wound healing during parasitic infections. Of additional interest was the observation that the drug, metformin, blocked Cox-1 expression and reduced expulsion of worm parasites from the intestine through its role in macrophage polarization. Metformin, however, has been shown to have beneficial affects on allergic disease in the lungs which suggests that Cox-1 is part of a cast of mediators regulating inflammation during an allergic response. This information is important to animal scientists interested in the mechanism of parasite control and also to clinicians that treat allergic disease in humans.

Technical Abstract: Interleukin (IL)-4 and IL-13 drive the polarization of macrophages towards an alternatively activated phenotype (M2) that is associated with the expression of potent pro-resolving mediators, such as prostaglandin D2 metabolites produced by the cyclooxygenase (Cox) pathway. Interestingly, while the expression of Cox-2 was significantly downregulated by IL-4, the protein expression of Cox-1 was upregulated in macrophages by increased polysomal translation of Ptgs-1 mRNA. This phenomenon not only challenged the dogma that Cox-1 was only developmentally regulated, but also demonstrated a novel mechanism where IL-4-dependent translation of Ptgs-1 mRNA involved the activation of the mTOR complex via 5 prime terminal oligopyrimidine (TOP) sequences at the transcription start site. Using specific chemical inhibitors, we demonstrate here that IL-4 increased the translation of Cox-1 via the c-fes-Akt-mTOR axis rather than the JAK/STAT pathway. Activation of AMPK by metformin or inhibition of mTOR by torin1 blocked the IL-4-dependent expression of Cox-1 and consequent ability of macrophages to polarize toward a M2 phenotype. However, use of 15d-PGJ2 partially rescued the effects of metformin suggesting the importance of Cox-1 in macrophage polarization as seen in a model of gastrointestinal helminth, Nippostrongylus brasiliensis, clearance. In summary, these studies suggest a novel paradigm where IL-4-dependent translational upregulation of Cox-1 expression may play a key role in tissue homeostasis and wound healing during Th2-mediated immune responses, such as parasitic infections.