Activation of Human Alveolar Macrophages via P2 Receptors: Coupling to Intracellular Ca2+ Increases and Cytokine Secretion

Abstract

Alveolar macrophages play a crucial role in the pathogenesis of inflammatory airway diseases. By the generation and release of different inflammatory mediators they contribute to both recruitment of different leukocytes into the lung and to airway remodeling. A potent stimulus for the release of inflammatory cytokines is ATP, which mediates its cellular effects through the interaction with different membrane receptors, belonging to the P2X and P2Y families. The aim of this study was to characterize the biological properties of purinoceptors in human alveolar macrophages obtained from bronchoalveolar lavages in the context of inflammatory airway diseases. The present study is the first showing that human alveolar macrophages express mRNA for different P2 subtypes, namely P2X1, P2X4, P2X5, P2X7, P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y13, and P2Y14. We also showed that extracellular ATP induced Ca2+ transients and increased IL-1β secretion via P2X receptors. Furthermore, extracellular nucleotides inhibited production of IL-12p40 and TNF-α, whereas IL-6 secretion was up-regulated. In summary, our data further support the hypothesis that purinoceptors are involved in the pathogenesis of inflammatory lung diseases.

Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses

“…IL1-β maturation and release in response to ATP in murine macrophages was confirmed by Perregaux and Gabel who reported a concomitant decrease in intracellular K + as a requisite [82]. In contrast to murine macrophages, in human macrophages the expression of TNF-α was reported to be downregulated, whereas IL-1β secretion was also here upregulated by extracellular nucleotides [78]. In rat alveolar macrophages, IL-1α, IL-1β, and IL-6 cytokine release was also reported to be facilitated by P2X7 receptor activation, while TNF-α release was not affected [83].…”

“…However, only P2Y 1 , P2Y 2 , P2Y 4 , P2X4, and P2X7 receptors were demonstrated to be functionally implicated in evoking ATP-mediated increases of cytosolic calcium levels [75][76][77]. In humans, alveolar macrophages were reported to express all P2 receptor subtypes except P2Y 12 , P2X2, P2X3, and P2X6 [78], whereas only, P2Y 1 , P2Y 2 , P2Y 11 , and P2X7 exhibit functional responses in inducing an intracellular calcium elevation.…”

Purinergic Signaling in the Airways

“…Moreover, extracellular ATP induces Ca 2ϩ transients and increased IL-1␤ and IL-6 secretion via P2X receptors, supporting the hypothesis that purinoreceptors may be involved in the pathogenesis of inflammatory lung diseases (see section VI) (Myrtek et al, 2008).…”

Electrical stimulation induces IL-6 in skeletal muscle through extracellular ATP by activating Ca2+signals and an IL-6 autocrine loop

“…These results convincingly suggest that the cellular signaling that leads to the expression of IL-6 in electrically stimulated myotubes is mediated by extracellular ATP, indicating that membrane depolarization, ATP signaling, and the expression of IL-6 are part of the same signaling pathway. Numerous reports have related the expression and secretion of IL-6 with extracellular nucleotides (10,31,60). Previously, we have reported the expression of IL-6 in skeletal myotubes after 30-min incubation with 500 M ATP (11).…”