IL-1β reduces cardiac lymphatic muscle contraction via COX-2 and PGE2 induction: Potential role in myocarditis

Mahmoud Al-Kofahi, Seiichi Omura, Ikuo Tsunoda, Fumitaka Sato, Felix Becker, Felicity N.E. Gavins, Matthew D. Woolard, Christopher Pattillo, David Zawieja, Mariappan Muthuchamy, Anatoliy Gashev, Israa Shihab, Mohamed Ghoweba, Pierre Yves Von der Weid, Yuping Wang, J. Steven Alexander

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


The role of lymphatic vessels in myocarditis is largely unknown, while it has been shown to play a key role in other inflammatory diseases. We aimed to investigate the role of lymphatic vessels in myocarditis using in vivo model induced with Theiler's murine encephalomyelitis virus (TMEV) and in vitro model with rat cardiac lymphatic muscle cells (RCLMC). In the TMEV model, we found that upregulation of a set of inflammatory mediator genes, including interleukin (IL)-1β tumor necrosis factor (TNF)-αand COX-2 were associated with disease activity. Thus, using in vitro collagen gel contraction assays, we decided to clarify the role(s) of these mediators by testing contractility of RCLMC in response to IL-1β and TNF-α individually and in combination, in the presence or absence of: IL-1 receptor antagonist (Anakinra); cyclooxygenase (COX) inhibitors inhibitors (TFAP, diclofenac and DuP-697). IL-1β impaired RCLMC contractility dose-dependently, while co-incubation with both IL-1β and TNF-α exhibited synergistic effects in decreasing RCLMC contractility with increased COX-2 expression. Anakinra maintained RCLMC contractility; Anakinra blocked the mobilization of COX-2 induced by IL-1β with or without TNF-α. COX-2 inhibition blocked the IL-1β-mediated decrease in RCLMC contractility. Mechanistically, we found that IL-1β increased prostaglandin (PG) E2 release dose-dependently, while Anakinra blocked IL-1β mediated PGE2 release. Using prostaglandin E receptor 4 (EP4) receptor antagonist, we demonstrated that EP4 receptor blockade maintained RCLMC contractility following IL-1β exposure. Our results indicate that IL-1β reduces RCLMC contractility via COX-2/PGE2 signaling with synergistic cooperation by TNF-α. These pathways may help provoke inflammatory mediator accumulation within the heart, driving progression from acute myocarditis into dilated cardiomyopathy.

Original languageEnglish (US)
Pages (from-to)1591-1600
Number of pages10
JournalBiomedicine and Pharmacotherapy
StatePublished - Nov 2018

Bibliographical note

Funding Information:
This work funded by a graduate research fellowship from the Center for Cardiovascular Diseases and Sciences, LSU Health Science Center-Shreveport (M. Al-Kofahi, F. Sato and S. Omura), a grant from the Department of Defense ( W81XWH-11-1-0577 , J.S. Alexander), the German Research Foundation (DFG, BE 5619/1-1, F. Becker), the National Institute of General Medical Sciences of the National Institutes of Health (NIH Award P30GM110703, I. Tsunoda), the Science Research Promotion Fund from the Promotion and Mutual Aid Corporation for Private Schools of Japan (F. Sato), the Faculty Assistance and Development Research Grants from the Kindai University Research Enhancement Grant (F. Sato and S. Omura), the KAKENHI from the Japan Society for the Promotion of Science ( JP17K15628 , F. Sato; and JP16H07356 , I. Tsunoda), and NIH/NHLBI ( ML125572-01A1 , F.N.E. Gavins).

Publisher Copyright:
© 2018 Elsevier Masson SAS


  • COX-2
  • IL-1β
  • Lymphatic contractility
  • Myocarditis
  • PGE
  • TNF-α


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