PMID- 28684424 OWN - NLM STAT- MEDLINE DCOM- 20170926 LR - 20230808 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 292 IP - 35 DP - 2017 Sep 1 TI - IL-4 up-regulates cyclooxygenase-1 expression in macrophages. PG - 14544-14555 LID - 10.1074/jbc.M117.785014 [doi] AB - Macrophages use various cell-surface receptors to sense their environment and undergo polarized responses. The cytokines, interleukin (IL)-4 and IL-13, released from T-helper type 2 (Th2) cells, drive macrophage polarization toward an alternatively activated phenotype (M2). This phenotype is associated with the expression of potent pro-resolving mediators, such as the prostaglandin (PG) D(2)-derived cyclopentenone metabolite, 15d-PGJ(2), produced by the cyclooxygenase (Ptgs; Cox) pathway. Interestingly, IL-4 treatment of bone marrow-derived macrophages (BMDMs) significantly down-regulates Cox-2 protein expression, whereas Cox-1 levels are significantly increased. This phenomenon not only challenges the dogma that Cox-1 is only developmentally regulated, but also demonstrates a novel mechanism in which IL-4-dependent regulation of Cox-1 involves the activation of the mechanistic target of rapamycin complex (mTORC). Using specific chemical inhibitors, we demonstrate here that IL-4-dependent Cox-1 up-regulation occurs at the post-transcriptional level via the Fes-Akt-mTORC axis. Activation of AMP-activated protein kinase (AMPK) by metformin, inhibition of mTORC by torin 1, or CRISPR/Cas9-mediated genetic knock-out of tuberous sclerosis complex-2 (Tsc2) blocked the IL-4-dependent expression of Cox-1 and the ability of macrophages to polarize to M2. However, use of 15d-PGJ(2) partially rescued the effects of AMPK activation, suggesting the importance of Cox-1 in macrophage polarization as also observed in a model of gastrointestinal helminth clearance. In summary, these findings suggest a new paradigm where IL-4-dependent up-regulation of Cox-1 expression may play a key role in tissue homeostasis and wound healing during Th2-mediated immune responses, such as parasitic infections. FAU - Shay, Ashley E AU - Shay AE AD - From the Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802. FAU - Diwakar, Bastihalli T AU - Diwakar BT AD - From the Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802. FAU - Guan, Bo-Jhih AU - Guan BJ AD - the Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio 44106. FAU - Narayan, Vivek AU - Narayan V AD - the Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, and. FAU - Urban, Joseph F Jr AU - Urban JF Jr AD - the United States Department of Agriculture (USDA), Agriculture Research Service, Beltsville Human Nutrition Research Center, Diet, Genomics, and Immunology Laboratory, Beltsville, Maryland 20705. FAU - Prabhu, K Sandeep AU - Prabhu KS AD - From the Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802, ksprabhu@psu.edu. LA - eng GR - R01 CA162665/CA/NCI NIH HHS/United States GR - R01 DK077152/DK/NIDDK NIH HHS/United States GR - T32 AI074551/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20170706 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (15-deoxyprostaglandin J2) RN - 0 (Enzyme Inhibitors) RN - 0 (Ligands) RN - 0 (Luminescent Proteins) RN - 0 (Membrane Proteins) RN - 0 (Recombinant Proteins) RN - 207137-56-2 (Interleukin-4) RN - 9100L32L2N (Metformin) RN - EC 1.14.99.1 (Cyclooxygenase 1) RN - EC 1.14.99.1 (Ptgs1 protein, mouse) RN - EC 2.7.11.1 (AMPK alpha1 subunit, mouse) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - RXY07S6CZ2 (Prostaglandin D2) SB - IM MH - AMP-Activated Protein Kinases/chemistry/*metabolism MH - Animals MH - Bone Marrow Cells/drug effects/immunology/metabolism/pathology MH - Cells, Cultured MH - Cyclooxygenase 1/genetics/metabolism MH - Enzyme Activation/drug effects MH - Enzyme Induction/drug effects MH - Enzyme Inhibitors/pharmacology MH - HEK293 Cells MH - Humans MH - Immunomodulation/drug effects MH - Interleukin-4/genetics/*metabolism MH - Ligands MH - Luminescent Proteins/genetics/metabolism MH - *Macrophage Activation/drug effects MH - Macrophages/drug effects/immunology/*metabolism/pathology MH - Male MH - Membrane Proteins/*agonists/genetics/metabolism MH - Metformin/pharmacology/therapeutic use MH - Mice, Inbred C57BL MH - *Models, Immunological MH - Nippostrongylus/drug effects/growth & development/immunology MH - Prostaglandin D2/analogs & derivatives/metabolism/therapeutic use MH - Recombinant Proteins/metabolism MH - Strongylida Infections/immunology/metabolism/pathology/prevention & control PMC - PMC5582846 OTO - NOTNLM OT - mTOR complex (mTORC) OT - metformin OT - parasite OT - post-transcriptional regulation OT - prostaglandin COIS- The authors declare that they have no conflicts of interest with the contents of this article EDAT- 2017/07/08 06:00 MHDA- 2017/09/28 06:00 PMCR- 2018/09/01 CRDT- 2017/07/08 06:00 PHST- 2017/03/07 00:00 [received] PHST- 2017/06/30 00:00 [revised] PHST- 2017/07/08 06:00 [pubmed] PHST- 2017/09/28 06:00 [medline] PHST- 2017/07/08 06:00 [entrez] PHST- 2018/09/01 00:00 [pmc-release] AID - S0021-9258(20)34192-2 [pii] AID - M117.785014 [pii] AID - 10.1074/jbc.M117.785014 [doi] PST - ppublish SO - J Biol Chem. 2017 Sep 1;292(35):14544-14555. doi: 10.1074/jbc.M117.785014. Epub 2017 Jul 6.