© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Stress-induced interleukin-6 release in mice is mast cell-dependent and more pronounced in Apolipoprotein E knockout mice
aDepartment of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA
bDepartment of Pathology, Tufts University School of Medicine, New England Medical Center, Boston, MA 02111, USA
cDivision of Endocrinology, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
* Corresponding author. Tel.: +1-617-636-6866; fax: +1-617-636-2456. theoharis.theoharides{at}tufts.edu
Objective: Interleukin-6 (IL-6) is elevated in the serum of patients with coronary artery disease (CAD) and acute coronary syndromes (ACS). Intracoronary release of IL-6 was reported in ACS that can also be triggered by acute stress. In rats, acute restraint stress increases serum IL-6 and histamine, both of which may derive from mast cells. The current study was carried out in order to determine any possible difference in stress-induced IL-6 release in atherosclerotic mice and the contribution of mast cells, corticotropin-releasing hormone (CRH) and urocortin (Ucn). Methods: C57BL/6J, W/Wv mast cell-deficient, Apolipoprotein E (ApoE) and CRH knockout (k/o) mice were stressed in plexiglass restraint chambers for 15 to 120 min. Serum corticosterone and IL-6 levels were measured. Some C57BL and ApoE k/o mice were pretreated with either the mast cell stabilizer disodium cromoglycate (cromolyn) or the peptide CRH receptor (CRH-R) antagonist Astressin. Cardiac mast cell activation was studied in both C57BL and ApoE k/o mice using light microscopy. Results: Acute stress increased serum IL-6 in mice, an effect much greater in ApoE k/o atherosclerotic mice. Stress-induced IL-6 release was absent in W/Wv mast cell-deficient mice and it was partially inhibited by cromolyn in C57BL and ApoE mice. Mast cells were found adjacent to atherosclerotic vessels in ApoE k/o mice and were activated after stress. CRH k/o mice released more IL-6 in response to stress than their wild types, but Astressin significantly inhibited IL-6 release. Stress-induced IL-6 release may, therefore, be at least partly due to peripheral Ucn and/or CRH, with Ucn possibly overcompensation for CRH deficiency. Conclusion: The present findings indicate that acute stress leads to mast cell-dependent serum IL-6 increase that may help explain stress-related coronary inflammation.
KEYWORDS Atherosclerosis; Coronary disease; Cytokines; Inflammation; Stress
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