IL‐1 induced release of Ca²⁺from internal stores is dependent on cell‐matrix interactions and regulates ERK activation

Abstract

The cellular mechanisms that modulate interleukin-1 (IL-1) signaling are not defined. In fibroblasts, IL-1 signaling is affected by the nature of cell-matrix adhesions including focal adhesions, adhesive domains that sequester IL-1 receptors. We conducted studies to elucidate which steps of cellular Ca2+ handling are affected by focal adhesions and by which mechanisms focal adhesions modulate IL-1-induced Ca2+ signals and ERK activation in human gingival fibroblasts. Cells were plated on poly-l-lysine or fibronectin and treated with tenascin, Hep-I, or SPARC peptides to inhibit focal adhesion formation. These treatments blocked IL-1 and thapsigargin-induced Ca2+ release from the endoplasmic reticulum, indicating that the ER-release pathway is focal adhesion dependent. Focal adhesions were also required for Ca2+ entry through store-operated channels and for IL-1-induced ERK activation. Thus interactions with the extracellular matrix and focal adhesion formation regulate IL-1-induced generation of intracellular Ca2+ signals that in turn are required for ERK activation.

Interleukin 1β-Induced Production of H2O2Contributes to Reduced Sigmoid Colonic Circular Smooth Muscle Contractility in Ulcerative Colitis

“…It has been reported that IL-1 may cause Ca 2ϩ release from intracellular stores through cell-matrix interactions in fibroblasts spread on surfaces coated with fibronectin (Wang et al, 2003). In isolated normal sigmoid muscle cells, however, we did not find that IL-1␤ caused cytosolic Ca 2ϩ increase under our experimental conditions.…”

Trypanosoma cruziInfection Activates Extracellular Signal-Regulated Kinase in Cultured Endothelial and Smooth Muscle Cells

“…IL-1␤ may induce the synthesis of ET-1 (12,32), which has also been demonstrated to act as an inducer of proinflammatory cytokines, and both ET-1 and IL-1␤ are capable of activating ERK1/2 ( Fig. 7) (60,65,66). In addition, cyclin D1, an important mediator of cell proliferation, is a downstream target of ERK1/2 and ET-1 (49,66).…”

SHP-2 Modulates Interleukin-1-induced Ca2+ Flux and ERK Activation via Phosphorylation of Phospholipase Cγ1

“…The deletion of SHP-2 by siRNA or by homologous recombination showed that SHP-2 is indeed required for both processes because IL-1-induced PLC␥1 phosphorylation and calcium release were almost completely blocked. We also tested whether calcium release, which is downstream of IL-1-induced SHP-2 and PLC phosphorylation, might affect these events, possibly by a negative feedback system involving the formation and functional attributes of focal adhesions (18). This notion was examined in cells that had been preincubated with BAPTA/AM to reduce IL-1-induced alterations of [Ca 2ϩ ] i .…”

“…However, the mechanisms whereby the various participants in this signaling pathway are marshaled to specific sites within the cell are not known. As noted earlier, IL-1-induced ERK activation is focal adhesion-restricted (9), requires the release of Ca 2ϩ from the endoplasmic reticulum (18), and may depend on the sequestration of signaling molecules such as Ras to endoplasmic reticulum membranes (17). Accordingly, we considered that focal adhesions and the endoplasmic reticulum may provide spatially discrete staging sites (19) that enable the SHP-2-dependent activation of ERK by IL-1.…”

“…are 3 cells from each of n ϭ 3 experiments. (9,18), but the spatial relationships between focal adhesions and sites of IL-1-induced Ca 2ϩ transients have not been described. We first determined whether IL-1-induced Ca 2ϩ signaling is restricted to focal adhesion sites.…”