Activation of tumor necrosis factor receptor 1 in airway smooth muscle: a potential pathway that modulates bronchial hyper-responsiveness in asthma?

Abstract

The cellular and molecular mechanisms that are involved in airway hyper-responsiveness are unclear. Current studies suggest that tumor necrosis factor (TNF)-alpha, a cytokine that is produced in considerable quantities in asthmatic airways, may potentially be involved in the development of bronchial hyper-responsiveness by directly altering the contractile properties of the airway smooth muscle (ASM). The underlying mechanisms are not known, but growing evidence now suggests that most of the biologic effects of TNF-alpha on ASM are mediated by the p55 receptor or tumor necrosis factor receptor (TNFR)1. In addition, activation of TNFR1 coupled to the tumor necrosis factor receptor-associated factor (TRAF)2-nuclear factor-kappaB (NF-kappaB) pathway alters calcium homeostasis in ASM, which appears to be a new potential mechanism underlying ASM hyper-responsiveness.

Figure 1

TNF-α enhances the contractile response to carbachol in murine tracheal rings. Murine tracheal rings were harvested and placed in culture overnight in an equal mixture of Ham F-12 and DMEM (vol/vol, 10% fetal bovine serum) in the presence or absence of TNF-α . Cumulative concentration-response curves to carbachol were measured on the cultured tracheal rings and compared among fresh controls (□ n = 18), or in the presence of 10 ng/ml (■ n = 12) or 50 ng/ml TNF-α (● n = 12), or in the absence of TNF-α (○ n = 7) for 24 h. Isometric measurements of tracheal reactivity were calculated as changes in milligram tensions per milligram weight (mg/mg) and expressed as percentage of 10^-5 mol/l carbachol-induced tensions. Although TNF-α appeared to augment carbachol-induced force generation in cultured murine tracheal rings, it is interesting to note that carbachol-induced increases in force generation were also increased as compared with those obtained in freshly harvested tissues. Results are expressed as mean± standard error of the mean. ^*P <0.05.

Figure 2

Potential intracellular mechanisms involved in the modulation of ASM hyper-responsiveness induced by TNF-α via TNFR1. Activation of TNFR1 coupled to the TRAF2-NF-κB pathway induces a delayed effect, in which long-term pretreatment with TNF-α enhances G-protein-coupled signal transduction, leading to increased calcium signals to contractile agonists. Activation of TNFR1 may also be involved in a rapid effect, in which short-term pretreatment with TNF-α enhances the calcium sensitization of intracellular contractile elements [20,21]. IP3, inositol-1,4,5-trisphosphate; PLC, phospholipase C.