Effects of Inflammatory Cytokines on Ca2+ Homeostasis in Airway Smooth Muscle Cells

  • Hisako MatsumotoEmail author


Crosstalk between airway inflammation and airway smooth muscle cells (ASMCs) contributes to airway hyperresponsiveness, a cardinal feature of asthma. The main putative mechanism underlying the agonist-induced intracellular Ca2+ ([Ca2+]i) transients in ASMCs is Ca2+ release from the sarcoplasmic reticulum (SR) via the inositol 1,4,5-trisphosphate (IP3) receptor and ryanodine receptor (RyR). Ca2+ depletion in SR then triggers store-operated Ca2+ entry (SOCE), Ca2+ influx from extracellular space. These mechanisms are modulated by inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-13, which have pivotal roles in asthma and chronic obstructive pulmonary disease (COPD).

TNF-α upregulates Gq and Gi protein expression, and interleukin (IL)-13 enhances histamine H1 receptor and cysteinyl leukotriene receptor 1, which enhances agonist-induced IP3/IP3 receptor signaling. Expression of CD38, which affects Ca2+ release from the SR via RyR, is upregulated with TNF-α, IL-13, and, to a lesser extent, interferon-γ and IL-1β pretreatment. TNF-α and IL-13 also augment SOCE and expression of caveolin-1, a scaffolding protein in caveolae, flask-shaped plasma membrane invaginations, which play a key role in Ca2+ signaling. Furthermore, both TNF-α and IL-13 decrease the expression of sarcoendoplasmic reticulum Ca2+ ATPase SERCA2, which transfers Ca2+ from the cytosol of the cell to the lumen of the SR to replenish Ca2+ in the SR. The downregulation of SERCA2 mimics altered Ca2+ homeostasis observed in asthma. This chapter describes the mechanisms that underlie the inflammatory cytokine-mediated modulation of [Ca2+]i in ASMCs.


Cytokines Interleukin-13 Tumor necrosis factor-α Thymic stromal lymphopoietin CD38 





Airway hyperresponsiveness


Airway smooth muscle cell


β2 adrenergic receptor


High-conductance Ca2+-activated potassium


Intracellular Ca2+


Cyclic ADP-ribose


Ca2+-induced Ca2+ release


Chronic obstructive pulmonary disease


Cysteinyl leukotriene receptor




Extracellular signal-regulated kinase


Human ASMC






Inositol 1,4,5-trisphosphate


Janus kinase


c-Jun N-terminal kinase


Leukotriene D4


Myosin light chain kinase


Myosin light chain phosphatase


Protein kinase A


Protein kinase C


Receptor-operated Ca2+ channels


Receptor-operated Ca2+ entry


Ryanodine receptor


Sarcoendoplasmic reticulum Ca2+ ATPase


Signal transducer and activator of transcription


Stromal-interacting molecule


Store-operated Ca2+ channel


Store-operated Ca2+ entry


Sarcoplasmic reticulum


Transforming growth factor


Tumor necrosis factor


Tumor necrosis factor receptor


Transient receptor potential channels


Thymic stromal lymphopoietin


Voltage-operated Ca2+ channel


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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  1. 1.Department of Respiratory MedicineKyoto UniversitySakyo-kuJapan

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