PGE2/EP4 signaling in peripheral immune cells promotes development of experimental autoimmune encephalomyelitis

Biochem Pharmacol. 2014 Feb 15;87(4):625-35. doi: 10.1016/j.bcp.2013.12.006. Epub 2013 Dec 16.


Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated inflammatory autoimmune disease model of multiple sclerosis (MS). The inflammatory process is initiated by activation and proliferation of T cells and monocytes and by their subsequent migration into the central nervous system (CNS), where they induce demyelination and neurodegeneration. Prostaglandin E2 (PGE2) - synthesized by cyclooxygenase 2 (COX-2) - has both pro- and anti-inflammatory potential, which is translated via four different EP receptors. We hypothesized that PGE2 synthesized in the preclinical phase by peripheral immune cells exerts pro-inflammatory properties in the EAE model. To investigate this, we used a bone marrow transplantation model, which enables PGE2 synthesis or EP receptor expression to be blocked specifically in peripheral murine immune cells. Our results reveal that deletion of COX-2 or its EP4 receptor in bone marrow-derived cells leads to a significant delay in the onset of EAE. This effect is due to an impaired preclinical inflammatory process indicated by a reduced level of the T cell activating interleukin-6 (IL-6), reduced numbers of T cells and of the T cell secreted interleukin-17 (IL-17) in the blood of mice lacking COX-2 or EP4 in peripheral immune cells. Moreover, mice lacking COX-2 or EP4 in bone marrow-derived cells show a reduced expression of matrix metalloproteinase 9 (MMP9), which results in decreased infiltration of monocytes and T cells into the CNS. In conclusion, our data demonstrate that PGE2 synthesized by monocytes in the early preclinical phase promotes the development of EAE in an EP4 receptor dependent manner.

Keywords: Cyclooxygenase-2; Interleukin-17; Interleukin-6; Matrix metalloproteinase 9; Multiple sclerosis; Prostaglandin E2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / immunology*
  • Bone Marrow Cells / pathology
  • Dinoprostone / biosynthesis
  • Dinoprostone / physiology*
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / pathology*
  • Female
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / immunology*
  • Monocytes / pathology
  • Receptors, Prostaglandin E, EP4 Subtype / biosynthesis
  • Receptors, Prostaglandin E, EP4 Subtype / physiology*
  • Signal Transduction / immunology*


  • Ptger4 protein, mouse
  • Receptors, Prostaglandin E, EP4 Subtype
  • Dinoprostone