Is there a role for prostanoid-mediated inhibition of IL-6 trans-signalling in the management of pulmonary arterial hypertension?

Biochem Soc Trans. 2019 Aug 30;47(4):1143-1156. doi: 10.1042/BST20190046. Epub 2019 Jul 24.

Abstract

Inflammation has been highlighted as a key factor in pulmonary arterial hypertension (PAH) development, particularly interleukin-6 (IL-6). IL-6 activates JAK-STAT signalling to induce transcription of pro-inflammatory and pro-angiogenic genes, enabling PAH progression, as well as the transcription of suppressor of cytokine signalling 3 (SOCS3) which limits IL-6 signalling. Current PAH therapies include prostanoid drugs which induce vasodilation via stimulating intracellular 3',5'-cyclic adenosine monophosphate (cAMP) levels. cAMP can also inhibit IL-6-mediated endothelial dysfunction via the induction of SOCS3. Thus, we propose that an important mechanism by which cAMP-mobilising prostanoid drugs limit PAH is by inhibiting IL-6-mediated pulmonary inflammation and remodelling via SOCS3 inhibition of IL-6 signalling. Further clarification may result in effective strategies with which to target the IL-6/JAK-STAT signalling pathway in PAH.

Keywords: IL-6; Janus kinase; cAMP; pulmonary hypertension.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Disease Models, Animal
  • Humans
  • Interleukin-6 / antagonists & inhibitors*
  • Interleukin-6 / metabolism*
  • Prostaglandins / pharmacology*
  • Pulmonary Arterial Hypertension / metabolism
  • Pulmonary Arterial Hypertension / therapy*
  • Signal Transduction / drug effects*
  • Suppressor of Cytokine Signaling 3 Protein / metabolism

Substances

  • Interleukin-6
  • Prostaglandins
  • Suppressor of Cytokine Signaling 3 Protein