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

Ashley E. Shay, Bastihalli T. Diwakar, Bo Jhih Guan, Vivek Narayan, Joseph F. Urban, K. Sandeep Prabhu

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)14544-14555
Number of pages12
JournalJournal of Biological Chemistry
Volume292
Issue number35
DOIs
StatePublished - Jan 1 2017

Fingerprint

Cyclooxygenase 1
Macrophages
Interleukin-4
Up-Regulation
Sirolimus
AMP-Activated Protein Kinases
Chemical activation
Tissue homeostasis
Clustered Regularly Interspaced Short Palindromic Repeats
Polarization
Prostaglandins D
Phenotype
Th2 Cells
Parasitic Diseases
Tuberous Sclerosis
Interleukin-13
Helminths
Metformin
Cell Surface Receptors
Cyclooxygenase 2

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Shay, A. E., Diwakar, B. T., Guan, B. J., Narayan, V., Urban, J. F., & Prabhu, K. S. (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
Shay, Ashley E. ; Diwakar, Bastihalli T. ; Guan, Bo Jhih ; Narayan, Vivek ; Urban, Joseph F. ; Prabhu, K. Sandeep. / IL-4 up-regulates cyclooxygenase-1 expression in macrophages. In: Journal of Biological Chemistry. 2017 ; Vol. 292, No. 35. pp. 14544-14555.
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Shay, AE, Diwakar, BT, Guan, BJ, Narayan, V, Urban, JF & Prabhu, KS 2017, 'IL-4 up-regulates cyclooxygenase-1 expression in macrophages', Journal of Biological Chemistry, vol. 292, no. 35, pp. 14544-14555. https://doi.org/10.1074/jbc.M117.785014

IL-4 up-regulates cyclooxygenase-1 expression in macrophages. / Shay, Ashley E.; Diwakar, Bastihalli T.; Guan, Bo Jhih; Narayan, Vivek; Urban, Joseph F.; Prabhu, K. Sandeep.

In: Journal of Biological Chemistry, Vol. 292, No. 35, 01.01.2017, p. 14544-14555.

Research output: Contribution to journalArticle

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AU - Shay, Ashley E.

AU - Diwakar, Bastihalli T.

AU - Guan, Bo Jhih

AU - Narayan, Vivek

AU - Urban, Joseph F.

AU - Prabhu, K. Sandeep

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