Tumor Necrosis Factor-α Potentiates Intraneuronal Ca2+ Signaling via Regulation of the Inositol 1,4,5-Trisphosphate Receptor

Keigan M Park,David I Yule,William J Bowers

doi:10.1074/jbc.m802209200

Keigan M Park, David I Yule + Show 1 more

Open Access

https://doi.org/10.1074/jbc.m802209200

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Abstract

Inflammatory events have long been implicated in initiating and/or propagating the pathophysiology associated with a number of neurological diseases. In addition, defects in Ca2+-handling processes, which shape membrane potential, influence gene transcription, and affect neuronal spiking patterns, have also been implicated in disease progression and cognitive decline. The mechanisms underlying the purported interplay that exists between neuroinflammation and Ca2+ homeostasis have yet to be defined. Herein, we describe a novel neuron-intrinsic pathway in which the expression of the type-1 inositol 1,4,5-trisphosphate receptor is regulated by the potent pro-inflammatory cytokine tumor necrosis factor-alpha. Exposure of primary murine neurons to tumor necrosis factor-alpha resulted in significant enhancement of Ca2+ signals downstream of muscarinic and purinergic stimulation. An increase in type-1 inositol 1,4,5-trisphosphate receptor mRNA and protein steady-state levels following cytokine exposure positively correlated with this alteration in Ca2+ homeostasis. Modulation of Ca2+ responses arising from this receptor subtype and its downstream effectors may exact significant consequences on neuronal function and could underlie the compromise in neuronal activity observed in the setting of chronic neuroinflammation, such as that associated with Parkinson disease and Alzheimer disease.

Highlights

The brain was once believed to be an immunoprivileged site, it is presently evident that immune-related activities, including inflammation, underlie normative and pathological brain function
TNF-␣ induces neuronal apoptosis though an excitotoxic mechanism mediated through alpha-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptors (9) and activates microglia, which may lead to the propagation of various neurological diseases (5)
Jun N-terminal protein kinase (JNK) Inhibition Abrogates the TNF-␣ Effect on Type-1 IP3R Expression and CCh-mediated Ca2ϩ Signals—The primary neurons grown in culture were found to express both the type-1 and type-2 TNF receptor subtypes, and because they are both known to couple to JNK, we examined the effect of a pharmacological inhibitor of JNK, SP600125, on the observed increases in type-1 IP3R mRNA, protein, and Ca2ϩ signals

Summary

Introduction

The brain was once believed to be an immunoprivileged site, it is presently evident that immune-related activities, including inflammation, underlie normative and pathological brain function. TNF-␣ treatment led to a significant up-regulation in peak height (2-fold, p Ͻ 0.05 by Student’s t test) of CCh-mediated Ca2ϩ signals at 24- and 48-h post exposure with a return to control peak levels at 72 h after initial cytokine application (Fig. 1, A and B).

Results

Conclusion