Cardiovascular Effect Of Interleukin-2 Via The Signal Transduction Pathway Of κ-Opioid Receptor In Rat

Cytokines are low molecular weight proteins that act as communication signals between cells of the immune system and as systemic mediators of the host's response to infection. Recent observations suggest that proinflammatory cytokines can modulate cardiovascular functions by a variety of mechanisms. Potential biological mechanisms underlying the cardiovascular effects include an alteration of cardiac p-receptor responsiveness, an increase in inducible nitric oxide synthase activity in cardiac muscle, associated with release of nitric oxide, NO and induction of apoptosis in myocytes. Interleukin-2 (IL-2) is produced by activated helper T lymphocytes and stimulates proliferation and effector functions in various cells of the immune system. Although cardiac effects of IL-2 have been reported, the mechanisms of action have not been fully elucidated. Negative inotropy of IL-2, partially mediated by NO, was observed in hamster papillary muscle. Further, clinical research has shown that IL-2 has negative inotropic properties in patients receiving IL-2 therapy. On the other hand, a positive inotropic response was induced by IL-2 in isolated rat atria, indirectlyby activating myocardial 3-adrenoceptors by release of catecholamines, and directly by increasing the production of second messenger cAMP.In the isolated rat heart, stimulation of cardiac K opioid receptors has been shown to induce ventricular ectopic beats and to reduce the force of ventricular contraction. In a previous, study, we found that IL-2 evoked responses similar to those of K opioid receptor agonists in the heart: perfusion with IL-2 at 200 U/ml induced arrhythmias in the isolated rat heart and cultured myocytes. Complex interactions between classical cytokines and opioids have been found in the nervous system. The neural effects of opioids can be changed by cytokines, while the effects of cytokines can be modulated by opioids. In PHA-stimulated human lymphocytes, the opioid receptor antagonist, naloxone, blunted the effect of IL-2. Thus, we hypothesised that there may be an interaction between IL-2 and opioids in the cardiovascular system.Therefore, the purpose of the present study was to determine whether the opioid receptor and its downstream pathway are involved in the cardiovascular effect of IL-2 and whether the effect of IL-2 under physiological or pathological conditions is changed.1 Effect of InterIeukin-2 on Contraction of Enzymatically Isolated Ventricular MyocytesCytokines play significant roles in some cardiovascular disorders, but direct myocardial effects of cytokines remain to be elucidated. In this study, we examined the effects and possible mechanisms of IL-2 on contraction of enzymatically isolated ventricular myocytes by using video tracking system. The parameters of cell contraction are as follows: peak velocity of cell shortening (+dL/dtmax); peak velocity of cell relengthening (-dL/dtmax); contraction amplitude (dL); end-diastolic cell length.Results: IL-2 (2.5-200 U/ml) depressed the contraction in a dose-dependent manner. IL-2decreased L/dtmax, dL and end-diastolic cell length. Inactive IL-2 at 50 U/ml did not significantly decrease L/dtmax, dL, or cell length. Pretreatment with the universal opioid receptor antagonist, naloxone (10 nmol/L) , or a specific K opioid receptor antagonist, nor-BNI (10 nmol/L), abolished the inhibitory effect of IL-2 on contraction; the specific 5-opioid receptor antagonist, naltrindole (1 jimol/L) had no effect. The effect of IL-2 was also abolished after pretreatment with pertussis toxin (PTX, 5 mg/L), but not by genistein (100 umol/L). Pretreatment with the phospholipase C inhibitor U73122 (5 umol/L) significantly inhibited the IL-2-induced depression of contraction.Conclusion: It is concluded that the effect of IL-2 on contraction of ventricular myocytes is mediated via the cardiac K opioid receptor, and the post-receptor signal transduction pathway includes a PTX sensitive G protein and phospholipase C.2 Effect of InterIeukin-2 on Intracellu...