Brain-Derived Neurotrophic Factor in TNF-α Modulation of Ca²⁺ in Human Airway Smooth Muscle

Abstract

There is increasing recognition that neurotrophin (NT) signaling occurs in non-neuronal tissues, including airway smooth muscle (ASM). We recently demonstrated that NTs, such as brain-derived neurotrophic factor (BDNF), enhance intracellular Ca 21 ([Ca 21 ] i ) and force regulation in human ASM. Increased NT expression has been observed in airway diseases, such as asthma and allergy. In the present study, we tested the hypothesis that NTs contribute to inflammation-induced enhancement of ASM contractility. Using human ASM cells and real-time fluorescence [Ca 21 ] i imaging, we examined the contribution of the high-affinity tropomyosin-related kinase and low-affinity, pan-NT p75NTR receptors to [Ca 21 ] i regulation under control conditions and after exposure to the proinflammatory cytokine TNF-a (20 ng/ml). Exposure to TNF-a enhanced [Ca 21 ] i responses to agonist (acetylcholine, histamine). Exposure to 10 nM BDNF for even 30 minutes substantially and synergistically enhanced TNF-a effects on [Ca 21 ] i responses to agonist. Small interfering RNA suppression of tropomyosin-related kinase substantially blunted the effect of BDNF on [Ca 21 ] i responses to agonist (with greater effect on Ca 21 influx via store-operated Ca 21 entry compared with sarcoplasmic reticulum Ca 21 release) in both control and TNF-a-exposed cells. However, p75NTR suppression by small interfering RNA had no significant effect on [Ca 21 ] i responses in either cell group. These novel data demonstrate that NTs influence ASM contractility, and suggest a potential role for NTs in airway diseases.

Brain-Derived Neurotrophic Factor in Cigarette Smoke–Induced Airway Hyperreactivity

“…However, as expected, the enhancing effects of 1 nM BDNF on [Ca 21 ] i responses were significantly blunted (P , 0.05; Figure 3A), confirming a role for TrkB in mediating the effects of BDNF on human ASM cells (10,15 Figure 3A). In contrast, p75NTR siRNA exerted only a small effect on either the BDNF or CSE enhancement of [Ca 21 ] i responses ( Figure 3B).…”

“…In this regard, evidence is increasing that neurotrophins and their receptors are expressed in a range of nonneuronal tissues, including the lung, as recently reviewed by Prakash and colleagues (22). We previously demonstrated, specific to ASM, that BDNF, TrkB, and p75NTR are all expressed by human ASM cells (10,15), and that BDNF nongenomically enhances [Ca 21 ] i responses to the agonist (10) and potentiates the effects of proinflammatory cytokines (15). The expression (11) and release (12) of BDNF were also demonstrated by other groups.…”

“…The techniques for the [Ca 21 ] i imaging of ASM cells were previously described (10,15). ASM cells were incubated with 5 mM fura-2/AM (Invitrogen), and calibrated real-time fluorescence measurements were obtained (20-30 cells/protocol).…”

“…NTs and their receptors have been identified in several non-neuronal systems, and we and others (10)(11)(12) have shown that human ASM expresses several NTs as well as their high-affinity receptors (e.g., tropomyosin-related kinase; Trk) and low-affinity receptors (e.g., pan-neurotrophin receptor p75NTR, a member of the TNF receptor superfamily (13)). Specifically, brain-derived neurotrophin factor (BDNF), which activates the high-affinity TrkB receptor (14), is expressed (10) and released (12) by human ASM, and appears to play a role in the regulation of intracellular calcium ([Ca 21 ] i ), and to force regulation under normal circumstances (10) as well as in the presence of inflammation (15). Furthermore, BDNF enhances ASM cell proliferation, potentiating the effects of proinflammatory cytokines (16).…”

Brain-Derived Neurotrophic Factor Serum Levels and Genotype: Association with Depression during Interferon-α Treatment

“…However, many immune and vascular endothelial cells also produce BNDF (Besser and Wank, 1999;Furuno and Nakanishi, 2006;Kerschensteiner et al, 1999;Kimata, 2005;Nakahashi et al, 2000;Prakash et al, 2009;Rezaee et al, 2010;Ziemssen et al, 2002); serum BDNF also correlates with leukocyte BDNF mRNA (Cattaneo et al, 2009), and systemic levels of BDNF are actually increased during attacks of multiple sclerosis (Liguori et al, 2009). Thus, there may be a complicated relationship between cortical and serum BDNF (Gass and Hellweg, 2010).…”