Stress-induced interleukin-6 release in mice is mast cell-dependent and more pronounced in Apolipoprotein E knockout mice

Cardiovasc Res. 2003 Jul 1;59(1):241-9. doi: 10.1016/s0008-6363(03)00340-7.


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/W(v) 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/W(v) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / genetics*
  • Coronary Disease / immunology*
  • Corticosterone / blood
  • Corticotropin-Releasing Hormone / blood
  • Corticotropin-Releasing Hormone / genetics
  • Corticotropin-Releasing Hormone / pharmacology
  • Cromolyn Sodium / pharmacology
  • Interleukin-6 / blood*
  • Mast Cells / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Peptide Fragments / pharmacology
  • Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors
  • Stress, Physiological / immunology*
  • Urocortins


  • Apolipoproteins E
  • Interleukin-6
  • Peptide Fragments
  • Receptors, Corticotropin-Releasing Hormone
  • Urocortins
  • astressin
  • Corticotropin-Releasing Hormone
  • Cromolyn Sodium
  • Corticosterone