Beta-arrestin 2 is an adaptor protein that leads termination of G protein activation and seems to be involved in the modulation of inflammatory response. Native hyaluronan (HA) degradation in pathological states, produces HA fragments able to stimulate pro-inflammatory effects in different cell types especially by interacting with the toll-like receptor 4 (TLR-4) and CD44. Particularly, TLR-4 activation induces the nuclear factor kappaB (NF-kB) translocation into the nucleus, that in turn, through the classical pathway mediated by the transforming growth factor activated kinase-1, (TAK-1), stimulates the inflammation response. We studied the involvement and role of beta-arrestin 2 in mouse chondrocytes stimulated with interleukin-1beta. Chondrocyte treatment with IL-1beta produced a significant increase in HA levels and degradation, and cyclic adenosine monophosphate (cAMP), up-regulated beta-arrestin 2, TAK-1, protein 38 mitogen-activated protein kinase (p38MAPK), and protein kinase A (PKA) mRNA expression and of the related protein levels. The NF-kB was also significantly activated, as well as the degradation of its inhibitory protein I-kappa-B-alpha (IkB-alpha), with a consequent transcription of pro-inflammatory mediators, such as tumor necrosis factor-alpha (TNF-alpha), and inducible nitric oxide synthase (iNOS). The treatment of IL-1beta-stimulated chondrocytes with beta-arrestin 2 inhibitor, significantly increased the inflammatory response, while the treatment with a specific TAK-1 inhibitor significantly reduced the inflammatory response. Interestingly, the anti-inflammatory action exerted by beta-arrestin-2 was mediated both through a direct inhibition of IkB-alpha and in part through cAMP and PKA activation mediated by p38MAPK up-regulation. The treatment of IL-1beta-stimulated chondrocytes with a p38MAPK and PKA specific inhibitors further confirmed the involvement of the p38MAPK pathways activation induced by beta-arrestin 2.

Beta Arrestin-2 negatively modulates inflammation response induced by Hyaluronan fragments in mouse chondrocytes stimulated with IL-1 beta

D'ASCOLA, ANGELA;AVENOSO, Angela;M. Scuruchi;CALATRONI, Alberto;CAMPO, Salvatore Giuseppe;CAMPO, Giuseppe Maurizio
2013

Abstract

Beta-arrestin 2 is an adaptor protein that leads termination of G protein activation and seems to be involved in the modulation of inflammatory response. Native hyaluronan (HA) degradation in pathological states, produces HA fragments able to stimulate pro-inflammatory effects in different cell types especially by interacting with the toll-like receptor 4 (TLR-4) and CD44. Particularly, TLR-4 activation induces the nuclear factor kappaB (NF-kB) translocation into the nucleus, that in turn, through the classical pathway mediated by the transforming growth factor activated kinase-1, (TAK-1), stimulates the inflammation response. We studied the involvement and role of beta-arrestin 2 in mouse chondrocytes stimulated with interleukin-1beta. Chondrocyte treatment with IL-1beta produced a significant increase in HA levels and degradation, and cyclic adenosine monophosphate (cAMP), up-regulated beta-arrestin 2, TAK-1, protein 38 mitogen-activated protein kinase (p38MAPK), and protein kinase A (PKA) mRNA expression and of the related protein levels. The NF-kB was also significantly activated, as well as the degradation of its inhibitory protein I-kappa-B-alpha (IkB-alpha), with a consequent transcription of pro-inflammatory mediators, such as tumor necrosis factor-alpha (TNF-alpha), and inducible nitric oxide synthase (iNOS). The treatment of IL-1beta-stimulated chondrocytes with beta-arrestin 2 inhibitor, significantly increased the inflammatory response, while the treatment with a specific TAK-1 inhibitor significantly reduced the inflammatory response. Interestingly, the anti-inflammatory action exerted by beta-arrestin-2 was mediated both through a direct inhibition of IkB-alpha and in part through cAMP and PKA activation mediated by p38MAPK up-regulation. The treatment of IL-1beta-stimulated chondrocytes with a p38MAPK and PKA specific inhibitors further confirmed the involvement of the p38MAPK pathways activation induced by beta-arrestin 2.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11570/2671215
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