IL-27p28 inhibits central nervous system autoimmunity by concurrently antagonizing Th1 and Th17 responses

J Autoimmun. 2014 May;50:12-22. doi: 10.1016/j.jaut.2013.08.003. Epub 2013 Sep 7.

Abstract

Central nervous system (CNS) autoimmunity such as uveitis and multiple sclerosis is accompanied by Th1 and Th17 responses. In their corresponding animal models, experimental autoimmune uveitis (EAU) and experimental autoimmune encephalomyelitis (EAE), both responses are induced and can drive disease independently. Because immune responses have inherent plasticity, therapeutic targeting of only one pathway could promote the other, without reducing pathology. IL-27p28 antagonizes gp130, required for signaling by IL-27 and IL-6, which respectively promote Th1 and Th17 responses. We therefore examined its ability to protect the CNS by concurrently targeting both effector responses. Overexpression of IL-27p28 in vivo ameliorated EAU as well as EAE pathology and reduced tissue infiltration by Th1 and Th17 cells in a disease prevention, as well as in a disease reversal protocol. Mechanistic studies revealed inhibition of Th1 and Th17 commitment in vitro and decreased lineage stability of pre-formed effectors in vivo, with reduction in expression of gp130-dependent transcription factors and cytokines. Importantly, IL-27p28 inhibited polarization of human T cells to the Th1 and Th17 effector pathways. The ability of IL-27p28 to inhibit generation as well as function of pathogenic Th1 and Th17 effector cells has therapeutic implications for controlling immunologically complex autoimmune diseases.

Keywords: Autoimmunity; IL-27p28; gp130.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Autoimmunity / drug effects*
  • Cell Lineage / immunology
  • Cell Movement / drug effects
  • Central Nervous System / immunology
  • Central Nervous System / pathology
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Gene Expression Regulation
  • Humans
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology
  • Interleukins / genetics
  • Interleukins / immunology*
  • Interleukins / pharmacology
  • Mice
  • Mice, Transgenic
  • Signal Transduction
  • Th1 Cells / drug effects
  • Th1 Cells / immunology*
  • Th1 Cells / pathology
  • Th17 Cells / drug effects
  • Th17 Cells / immunology*
  • Th17 Cells / pathology
  • Transcription Factors / genetics
  • Transcription Factors / immunology
  • Uveitis / genetics
  • Uveitis / immunology*
  • Uveitis / pathology

Substances

  • Il27 protein, mouse
  • Interleukin-6
  • Interleukins
  • Transcription Factors