Histamine reverses IL-5-afforded human eosinophil survival by inducing apoptosis: Pharmacological evidence for a novel mechanism of action of histamine

Abstract

A c c e p t e d m a n u s c r i p tCaspase activities were assessed by using commercial Caspase-Glo ® 3/7, 8, and 9 luminescence assays.Histamine (10-100 µM) partially reversed IL-5-induced human eosinophil survival by enhancing apoptosis as assessed by measuring the relative DNA content of PI-stained cells.This effect was not mediated through any of the known histamine receptors or through nonspecific activation of 5-hydroxytryptamine receptors or α-adrenoceptors. Moreover, the reversal of IL-5-inhibited eosinophil apoptosis by histamine seemed not to utilize the conventional intracellular second messenger pathways including cyclic AMP, protein kinase A or phospholipase C. Inhibition of caspase 6 and caspases 1, 10 or 12 reversed the effects of histamine but also inhibited apoptosis in general.In conclusion, the data presented herein indicate that histamine induces human eosinophil apoptosis in the presence of a survival-prolonging cytokine by a mechanism that does not apparently involve the activation of any of the currently known histamine receptor subtypes.The possibility exists that another, as yet unidentified, histamine receptor may exist in human eosinophils that regulates survival, although the participation of histamine receptorindependent mechanisms cannot be excluded. 3A c c e p t e d m a n u s c r i p t

Physical interactions between mast cells and eosinophils: a novel mechanism enhancing eosinophil survival in vitro

“…In our cultures, GM‐CSF slightly increased the viability of MCs alone, yet it may have negated their ability to sustain Eos in co‐culture. Indeed, activation of some MC phenotypes could counteract Eos viability: Histamine from stimulated MCs attenuates IL‐5‐induced survival of Eos (34), and MC‐derived prostaglandin D 2 and J 2 induce Eos apoptosis (35). The MC influence on Eos survival is likely a net effect of several signals reflecting the cell activation state and cytokine/mediator milieu and could therefore be altered under diverse pathophysiologic settings.…”

Histamine 1 Receptor Blockade Enhances Eosinophil-Mediated Clearance of Adult Filarial Worms

“…One possibility is that HR1 blockade may have enhanced eosinophil survival. Data from one in vitro study suggests histamine signaling reverses IL-5 afforded eosinophil survival [ 25 ]. A second hypothesis to explain increased eosinophil numbers at the site of worm infection is enhancement of eosinophil chemotaxis by blockade of HR1 signaling.…”

Regulation of Spontaneous Eosinophil Apoptosis—A Neglected Area of Importance

“…52,75,96,100 Caspase-9, accounted as the initiator caspase activated in response to mitochondrial apoptotic pathway, has been shown to be processed during spontaneous and induced apoptosis. 52,84,[101][102][103] However, its inhibition by Z-LEHD-FMK did not prevent spontaneous apoptosis or FasL-mediated apoptosis, suggesting that it may not function as a critical initiator caspase in these pathways. 84,101 However, a possibility exists that the inhibitor used was inefficient, because according to our data it inhibited only 65% of caspase-9 activity in eosinophils.…”

“…But similar to caspase-9, its inhibition did not prevent apoptotic events during spontaneous apoptosis. 52,84,[101][102][103] Altogether, the initiator caspase responsible for the proceeding of spontaneous apoptosis is not clear. In neutrophils, activation of caspase-8 was shown to be dependent on initiator caspase-9 104 and may be actually activated by effector caspase-3, as previously described.…”