The down regulation by propranolol selleck chemicals does not appear to be due to cytotoxicity of the antagonist since there is no difference in viabilities between the pro pranolol treated and untreated cell cultures. It was inter esting to see that propranolol caused a reduction of production of IL 13 to an amount that was much lower than that treated with IL 1 only. It may be that epinephrine induced enhancement of IL 13 production is more sensitive to the propranolol blocking. Activated NF B has been demonstrated in atheromatous plaques and has been shown to play a role in atherogenesis. To study the mechanism of the enhancing effect of epinephrine on proatherogenic cytokine production from IL 1 induced mast cells, NF B and p38 MAPK activations were investigated. Control samples and epinephrine alone samples did not induce NF B activation.

However, a marked increase in NF B activation was observed in samples stimulated with IL 1 and IL 1 plus epinephrine. NF B activation was seen early at one hour and began to fade by two hours. NF B also was not increased by the addition of epine phrine to IL 1 and even seemed to decrease it at both decreased IL 1 induced cytokine production in mast cells. Taken all together, these results indicate that 2 adrenoceptor antagonists and glucocorticoids may have clinical potential in stress mediated disease and atherogenesis. All the signaling pathways induced by IL 1 and epine phrine in mast cells are complex and beyond the scope of this manuscript. However, two important inflammatory pathways, NF B and p38 MAPK, have been shown.

IL 1 release from immune challenge and epinephrine elevated from stress response can jointly stimulate mast cells to increase IL 6, 8, and 13 production above that which is Schematic presentation showing the possible route of IL 6, time points suggesting that NF B is needed for cytokine induction but not for the enhancing effect. The presence of phosphorylated p38 MAPK was Entinostat greatly increased in the epinephrine and IL 1 plus epinephrine samples but only minimally activated with IL 1 alone at a 30 minute incu bation time point. SB203580 blocked the IL 1 and IL 1 plus epinephrine effect on IL 6, IL 8, and IL 13 expression suggesting that p38 plays an important role in signaling from both IL 1 and epinephrine. The double stimulation of p38, early by IL 1 and later by epine phrine, may explain the enhancing effect on the produc tion of IL 6, IL 8, and IL 13 in mast cells. The enhancing effect of epinephrine on proatherogenic cytokine production was also down regulated by immu nosupressants, such as Dex.