beta2-Adrenoceptor-mediated suppression of human intestinal mast cell functions is caused by disruption of filamentous actin dynamics.
Previous studies indicated potent inhibitory effects of beta2-adrenoceptor (beta2AR) activation on the immunological mediator release of mast cells (MC). Here, we studied effects of beta2AR agonists on human MC mediator release, and in particular on MC proliferation, adhesion, and migration. MC were isolated from human intestinal mucosa, purified, and cultured in the presence of stem cell factor (SCF). beta2AR activation by epinephrine, norepinephrine, and salbutamol suppressed the IgE receptor-dependent release of histamine, lipid mediators, and TNF-alpha, and inhibited SCF-dependent MC proliferation and migration. Moreover, beta2-adrenergic stimulation interfered with MC adhesion to fibronectin and human endothelial cells. Using fluorescent phallacidin, we found that beta2AR activation reduced the amount of filamentous actin (F-actin) within minutes, whereas MC stimulation by either IgE receptor cross-linking or SCF caused F-actin accumulation. Interestingly, this activation-induced F-actin increase was abolished by previous beta2-adrenergic stimulation. Finally, we demonstrated that disruption of the F-actin cytoskeleton by latrunculin B mimicked the effects of beta2AR agonists on MC adhesion and migration. Our results argue for an important role of F-actin interference in beta2AR-mediated MC inhibition. Furthermore, the data support the concept of neuroimmune interactions regulating intestinal MC distribution, density, and functionality in vivo.
Gebhardt
Thomas
T
Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover, Hannover, Germany.
Gerhard
Ralf
R
Bedoui
Sammy
S
Erpenbeck
Veit J
VJ
Hoffmann
Matthias W
MW
Manns
Michael P
MP
Bischoff
Stephan C
SC
D000199:Actins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D058666:Adrenergic beta-2 Receptor Agonists; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology*; D008407:Mast Cells / Q000276:immunology / Q000502:physiology*; D018343:Receptors, Adrenergic, beta-2 / Q000276:immunology / Q000502:physiology*
D000199:Actins; D058666:Adrenergic beta-2 Receptor Agonists; D018343:Receptors, Adrenergic, beta-2