title: Beta-arrestin-2 negatively modulates inflammation response in mouse chondrocytes induced by 4-mer hyaluronan oligosaccharide.
abstract: Beta-arrestin-2 is an adaptor protein that terminates G protein activation and seems to be involved in the modulation of the inflammatory response. Small hyaluronan (HA) fragments, such as 4-mer HA oligosaccharides, are known to interact with the toll-like receptor-4 (TLR-4) with consequent activation of the nuclear factor kappaB (NF-kB) that in turn stimulates the inflammation response. NF-kB activation is mediated by different pathways, in particular by the transforming growth factor-activated kinase-1 (TAK-1). Conversely, increased levels of protein kinase A (PKA), induced by cyclic adenosine monophosphate (cAMP), seem to inhibit NF-kB activation. We studied the involvement and role of beta-arrestin-2 in mouse chondrocytes stimulated with 4-mer HA fragments. The exposure of chondrocytes to 4-mer HA produced a significant up-regulation in TLR-4, cAMP, beta-arrestin-2, TAK-1, protein 38 mitogen-activated protein kinase (p38MAPK), and PKA, both in terms of mRNA expression and of the related protein levels. NF-kB was significantly activated, thereby producing the transcription of pro-inflammatory mediators, including tumor necrosis factor alpha, interleukin-6, and interleukin-17. The treatment of 4-mer HA-stimulated chondrocytes with antibodies against beta-arrestin-2 and/or a specific PKA inhibitor, significantly increased the inflammatory response, while the treatment with a specific p38MAPK inhibitor significantly reduced the inflammatory response. Interestingly, the anti-inflammatory action exerted by beta-arrestin-2 appeared to be mediated in part through the direct inhibition of p38MAPK, preventing NF-kB activation, and in part through cAMP and PKA activation primed by G protein signaling, which exerted an inhibitory effect on NF-kB. Taken together, these results could be useful for future anti-inflammatory strategies.
authors.affiliation: Department of Biomedical Sciences and Morphological and Functional Images, Section of Medical Biotechnologies and Preventive Medicine, School of Medicine, University of Messina, Policlinico Universitario, Torre Biologica, 5° piano, Via C. Valeria, 98125, Messina, Italy, gcampo@unime.it.
authors.forename: Giuseppe M
authors.initials: GM
authors.lastname: Campo
authors.forename: Angela
authors.initials: A
authors.lastname: Avenoso
authors.forename: Angela
authors.initials: A
authors.lastname: D'Ascola
authors.forename: Michele
authors.initials: M
authors.lastname: Scuruchi
authors.forename: Alberto
authors.initials: A
authors.lastname: Calatroni
authors.forename: Salvatore
authors.initials: S
authors.lastname: Campo
mesh_terms: D000818:Animals; D019390:Arrestins / Q000502:physiology*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000276:immunology / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006820:Hyaluronic Acid / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism; D018836:Inflammation Mediators / Q000502:physiology*; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008811:Mice, Inbred DBA; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C000605258:Arrb2 protein, mouse; D019390:Arrestins; D018836:Inflammation Mediators; D020381:Interleukin-17; D015850:Interleukin-6; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D006820:Hyaluronic Acid; D017868:Cyclic AMP-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases