Regulation of interleukin 1 signalling through integrin binding and actin reorganization: disparate effects on NF-κB and stress kinase pathways

Abstract

Interleukin 1 (IL-1)-mediated gene regulation is dependent on cell-matrix interactions. Both IL-1-activated pathways, nuclear factor kappaB (NF-kappaB) and the stress-activated protein kinase (SAPK), can be regulated by cell adhesion and changes in the cytoskeleton, suggesting that cell-matrix effects on IL-1 responses are initiated in part though effects on signal transduction. Here we show that IL-1-induced transient alterations in cell shape and in the cytoskeleton in fibronectin attached cells are correlated with effects on peak activity of NF-kappaB and SAPK. Cells on fibronectin showed a 1.5-2-fold enhancement in IL-1-induced NF-kappaB activity compared with levels in cells on poly(l-lysine) or bare tissue culture plates. The effect was increased with increasing concentrations of fibronectin and was most prominent at lower concentrations of IL-1. In contrast, fibronectin attachment caused an approx. 50% decrease in the IL-1 activation of SAPK, eliminating the peak activity after 15 min of stimulation with IL-1. IL-1-induced NF-kappaB activity showed a successive, substratum-independent increase during 4 h of attachment and spreading, whereas the inhibitory effect of fibronectin on the SAPK pathway was induced at the initial stages of attachment. Further, the addition of a peptide containing the motif RGD resulted in a 40% decrease in NF-kappaB activity in cells on fibronectin, largely accounted for by an effect on the p50/p65 heterodimer. Similarly, blocking of integrin aggregation by RGD-containing peptide resulted in a total abrogation of the fibronectin effect on IL-1-induced SAPK activity. The results demonstrate disparate effects of cell adhesion on the activation by IL-1 of the NF-kappaB and SAPK pathways. Thus fibronectin attachment causes an up-regulation of NF-kappaB activity in the presence of IL-1, whereas in contrast it results in a pronounced decrease in IL-1-induced SAPK activity.

The IL-1 receptor and Rho directly associate to drive cell activation in inflammation

“…IL-1 downregulated proteoglycan synthesis and stimulated IL-6 gene expression in fibroblasts grown on fibronectin, but not on vitronectin or collagen, suggesting that specific matrix molecules regulate IL-1-activated signaling (18). Finally, IL-1-induced alterations in NF-κB and stress-activated protein kinase (SAPK) activities in cells grown on fibronectin were inhibited when cells were cultured on poly-L-lysine or when RGD-containing peptides were included (16). Rho family GTPases, by controlling adhesion complex assembly and consequent signaling activity, may function as molecular switches that cluster signaling molecules in specific architectures necessary for persistent cell activation (54).…”

“…IL-1 receptors cluster at focal adhesions (13), and IL-1 stimulates rapid phosphorylation of talin, a structural component of focal complexes, as well as the activation of focal adhesion kinase p125FAK (14,15). Mesenchymal cell adhesion to fibronectin regulates IL-1-dependent inhibition of proteoglycan synthesis, stimulation of nuclear factor-κB (NF-κB) activity, and induction of collagen and IL-6 gene expression (16)(17)(18). IL-1-induced calcium flux in fibroblasts and chondrocytes is dependent on attachment to matrix and formation of focal adhesions (15,19).…”

Differential expression of the IL-1 system components during in vitro myogenesis: Implication of IL-1β in induction of myogenic cell apoptosis

“…ICE cleaves actin, 46 and IL-1 induces disorganization of the actin cytoskeleton of fibroblasts in vitro. 47 The spreading phenotype of myogenic cells exposed to IL-1b also reflected cytoskeletal changes. Such an effect of IL-1b is reminiscent of in vivo IL-1b expression by muscle fibres in pathologic states characterized by marked myofibrillar loss.…”

The Protein Tyrosine Phosphatase SHP-2 Regulates Interleukin-1-induced ERK Activation in Fibroblasts

“…The adapter protein MyD88 then recruits Toll-interacting protein (16) and the IL-1 receptor-associated kinases (17)(18)(19)(20), which initiate downstream signaling. Engagement of the IL-1 receptor initiates multiple signaling events implicated in the pathogenesis of chronic inflammatory diseases, including: (i) phosphorylation of multiple kinases and IL-1R 1 -associated proteins (21,22), (ii) Ca 2ϩ flux (23), (iii) reorganization of the actin cytoskeleton (24), and (iv) activation of three members of the MAPK family, ERK, JNKs/SAPKs, and p38 MAP kinases (25)(26)(27).…”