Attenuation of experimental autoimmune myocarditis by blocking T cell activation through 4-1BB pathway

J Mol Cell Cardiol. 2009 May;46(5):719-27. doi: 10.1016/j.yjmcc.2009.02.003. Epub 2009 Feb 20.


4-1BB, a member of the tumor necrosis factor receptor (TNFR) family, binds the 4-1BB ligand (4-1BBL), works as a costimulatory molecule, and regulates T cell-mediated immune responses. Although inflammation is an essential pathological feature of myocarditis, the role of 4-1BB in experimental autoimmune myocarditis (EAM) remains unclear. Lewis rats were immunized on day 0 with purified porcine cardiac myosin to establish EAM. 4-1BB-immunoglobulin (4-1BBIg) was administered intraperitoneally (n=6) a total of 9 times (3 times per week). Rats were killed on day 21 to study effects of 4-1BB/4-1BBL pathway blockade. For controls, isotype-matched human IgG was administered in other EAM rats (n=6). Histologic and echocardiographic examination showed development of EAM attenuated by 4-1BBIg. Suppression of mRNA expression for IL-1alpha, IL-1beta, IL-4, IL-6, and TNF-alpha was noted in the heart tissue treated with 4-1BBIg. Treatment with 4-1BBIg reduced production of Th1-type cytokines, and inhibited T cell proliferation in vitro. In the 4-1BB signaling pathway in splenocytes, 4-1BBIg suppressed JNK, p38, and IkappaB activity but not that of ERK1/2. Blockade of T cell activation through the 4-1BB/4-1BBL pathway regulates development of EAM; therefore, 4-1BB may be an effective target for treating myocarditis.

MeSH terms

  • 4-1BB Ligand / metabolism
  • 4-1BB Ligand / pharmacology
  • Animals
  • Autoimmune Diseases / enzymology
  • Autoimmune Diseases / immunology*
  • Autoimmune Diseases / pathology
  • Autoimmune Diseases / prevention & control*
  • Cell Proliferation / drug effects
  • Cytokines / genetics
  • Cytokines / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Regulation / drug effects
  • Humans
  • I-kappa B Kinase / metabolism
  • Immunohistochemistry
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology*
  • Male
  • Myocarditis / enzymology
  • Myocarditis / immunology*
  • Myocarditis / pathology
  • Myocarditis / prevention & control*
  • Myocardium / enzymology
  • Myocardium / pathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Inbred Lew
  • Sus scrofa
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • Th1 Cells / metabolism
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • 4-1BB Ligand
  • Cytokines
  • RNA, Messenger
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • I-kappa B Kinase
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases