Neurotensin and CRH Interactions Augment Human Mast Cell Activation

Konstantinos–Dionysios Alysandratos,Bodi Zhang,Agatha Critchfield,Theoharis C. Theoharides,Nikolaos Sismanopoulos,Hailing Yang,Asimenia Angelidou,Shahrzad Asadi,T. Mark Doherty

doi:10.1371/journal.pone.0048934

Abstract

Stress affects immunity, but the mechanism is not known. Neurotensin (NT) and corticotropin-releasing hormone (CRH) are secreted under stress in various tissues, and have immunomodulatory actions. We had previously shown that NT augments the ability of CRH to increase mast cell-dependent skin vascular permeability in rodents. Here we show that NT triggered human mast cell degranulation and significantly augmented CRH-induced vascular endothelial growth factor (VEGF) release. Investigation of various signaling molecules indicated that only NF-κB activation was involved. These effects were blocked by pretreatment with the NTR antagonist SR48692. NT induced expression of CRH receptor-1 (CRHR-1), as shown by Western blot and FACS analysis. Interestingly, CRH also induced NTR gene and protein expression. These results indicate unique interactions among NT, CRH, and mast cells that may contribute to auto-immune and inflammatory diseases that worsen with stress.

Highlights

Stress affects immunity, but its mechanism is not understood
NT stimulates human mast cell degranulation Here we show that NT (1 and 10 mM) triggered statistically significant degranulation (p,0.01) of human LAD2 mast cells as measured by b-hex secretion at 30 min (Fig. 1A)
In view of the fact that NT can enhance the effect of corticotropin-releasing hormone (CRH) on skin vascular permeability [11], we investigated the effect of these peptides on vascular endothelial growth factor (VEGF) release from LAD2 mast cells

Summary

Introduction

Neurotensin (NT) is a vasoactive peptide originally isolated from the brain [1] and has been implicated in immunity [2,3], but its role in the stress response has not been investigated. NT is increased in the skin following acute stress, stimulates skin mast cells and increases vascular permeability in rodents [4]. NT administration increases vascular permeability in isolated rat skin [5] and in skin blisters through mast cell activation [6]. NT stimulates rodent mast cells to secrete histamine and elevates histamine plasma levels through NTR [7,8,9]. NT is rapidly degraded by mast cell proteases [10,11] implying tight regulation of its activity

Methods

Results

Conclusion