| Title | Toll-like receptor 2 activation by bacterial peptidoglycan-associated lipoprotein activates cardiomyocyte inflammation and contractile dysfunction. | | Author(s) | Zhu X, Bagchi A, Zhao H, Kirschning CJ, Hajjar RJ, Chao W, Hellman J, Schmidt U | | Institution | From the Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, MA (XZ, AB, HZ, WC, JH, US); Institute of Medical Microbiology, Immunology, and Hygiene, Technical University of Munich, Munich, Germany (CJK); and the Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA (RJH). | | Source | Crit Care Med 2007 Jan 23. | | Abstract | OBJECTIVE:: Although cardiac dysfunction plays an important role in the pathogenesis of sepsis, the mechanisms that underlie cardiac dysfunction in sepsis remain poorly understood. Bacterial peptidoglycan-associated lipoprotein (PAL), an outer-membrane protein of Gram-negative bacteria, was recently found to be released into the bloodstream in sepsis and to cause inflammation and death in mice. The present studies assessed the effects of PAL on cardiomyocyte function and its signal transduction in cardiomyocytes.
DESIGN:: Randomized prospective animal study.
SETTING:: Research laboratory.
SUBJECTS:: Male C57BL/6 mice, B6;129S-Tnfrsf1a Tnfrsf1b/ J knockout mice, Toll-like receptor 2 (TLR2) knockout mice, and myeloid differentiation factor 88 (MyD88) knockout mice.
INTERVENTIONS:: None.
MEASUREMENTS AND RESULTS:: Immunohistochemical staining and immunoblot analysis indicated that intravenously injected PAL bound to myocardium. Injection of PAL decreased cardiac function in vivo. Challenge with PAL altered cell shortening and Ca transients in isolated mouse cardiomyocytes but not in cardiomyocytes isolated from TLR2 and MyD88 mice. Cytokine profiling arrays demonstrated that tumor necrosis factor-alpha (TNFalpha), granulocyte colony-stimulating factor, and interferon-gamma production were elevated in PAL-treated cardiomyocytes. Increased TNFalpha production was abolished in MyD88 cardiomyocytes but restored by adenovirally mediated expression of MyD88. PAL did not affect cell shortening and Ca cycling in cardiomyocytes obtained from mice deficient for TNFalpha receptor (TNFR) 1 and TNFR2 (TNFR1/2).
CONCLUSION:: Our data reveal that PAL uses the TLR2/MyD88 signaling cascade to induce cardiomyocyte dysfunction and inflammatory responses and that TNFalpha is a major mediator of PAL-induced dysfunction in cardiomyocytes. These studies suggest that circulating PAL and other TLR2 agonists may contribute to cardiac dysfunction in sepsis. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 17255871 |
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