The activin-follistatin anti-inflammatory cycle is deregulated in synovial fibroblasts.
Activins
/ biosynthesis
Animals
Arthritis, Rheumatoid
/ genetics
Blotting, Western
Cells, Cultured
Disease Models, Animal
Enzyme-Linked Immunosorbent Assay
Fibroblasts
/ metabolism
Follistatin
/ biosynthesis
Gene Expression Regulation
Humans
Immunohistochemistry
Mice
Mice, SCID
RNA
/ genetics
Synovial Membrane
/ metabolism
Activin A
Follistatin
Rheumatoid arthritis
Synovial fibroblasts
Journal
Arthritis research & therapy
ISSN: 1478-6362
Titre abrégé: Arthritis Res Ther
Pays: England
ID NLM: 101154438
Informations de publication
Date de publication:
10 06 2019
10 06 2019
Historique:
received:
18
01
2019
accepted:
26
05
2019
entrez:
12
6
2019
pubmed:
12
6
2019
medline:
30
5
2020
Statut:
epublish
Résumé
Activin A and follistatin exhibit immunomodulatory functions, thus affecting autoinflammatory processes as found in rheumatoid arthritis (RA). The impact of both proteins on the behavior of synovial fibroblasts (SF) in RA as well as in osteoarthritis (OA) is unknown. Immunohistochemical analyses of synovial tissue for expression of activin A and follistatin were performed. The influence of RASF overexpressing activin A on cartilage invasion in a SCID mouse model was examined. RASF and OASF were stimulated with either IL-1β or TNFα in combination with or solely with activin A, activin AB, or follistatin. Protein secretion was measured by ELISA and mRNA expression by RT-PCR. Smad signaling was confirmed by western blot. In human RA synovial tissue, the number of activin A-positive cells as well as its extracellular presence was higher than in the OA synovium. Single cells within the tissue expressed follistatin in RA and OA synovial tissue. In the SCID mouse model, activin A overexpression reduced RASF invasion. In human RASF, activin A was induced by IL-1β and TNFα. Activin A slightly increased IL-6 release by unstimulated RASF, but decreased protein and mRNA levels of follistatin. The observed decrease of cartilage invasion by RASF overexpressing activin A in the SCID mouse model appears to be mediated by an interaction between activin/follistatin and other local cells indirectly affecting RASF because activin A displayed certain pro-inflammatory effects on RASF. Activin A even inhibits production and release of follistatin in RASF and therefore prevents itself from being blocked by its inhibitory binding protein follistatin in the local inflammatory joint environment.
Sections du résumé
BACKGROUND
Activin A and follistatin exhibit immunomodulatory functions, thus affecting autoinflammatory processes as found in rheumatoid arthritis (RA). The impact of both proteins on the behavior of synovial fibroblasts (SF) in RA as well as in osteoarthritis (OA) is unknown.
METHODS
Immunohistochemical analyses of synovial tissue for expression of activin A and follistatin were performed. The influence of RASF overexpressing activin A on cartilage invasion in a SCID mouse model was examined. RASF and OASF were stimulated with either IL-1β or TNFα in combination with or solely with activin A, activin AB, or follistatin. Protein secretion was measured by ELISA and mRNA expression by RT-PCR. Smad signaling was confirmed by western blot.
RESULTS
In human RA synovial tissue, the number of activin A-positive cells as well as its extracellular presence was higher than in the OA synovium. Single cells within the tissue expressed follistatin in RA and OA synovial tissue. In the SCID mouse model, activin A overexpression reduced RASF invasion. In human RASF, activin A was induced by IL-1β and TNFα. Activin A slightly increased IL-6 release by unstimulated RASF, but decreased protein and mRNA levels of follistatin.
CONCLUSION
The observed decrease of cartilage invasion by RASF overexpressing activin A in the SCID mouse model appears to be mediated by an interaction between activin/follistatin and other local cells indirectly affecting RASF because activin A displayed certain pro-inflammatory effects on RASF. Activin A even inhibits production and release of follistatin in RASF and therefore prevents itself from being blocked by its inhibitory binding protein follistatin in the local inflammatory joint environment.
Identifiants
pubmed: 31182152
doi: 10.1186/s13075-019-1926-7
pii: 10.1186/s13075-019-1926-7
pmc: PMC6558802
doi:
Substances chimiques
Follistatin
0
activin A
0
Activins
104625-48-1
RNA
63231-63-0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
144Subventions
Organisme : Deutsche Forschungsgemeinschaft
ID : SFB 1009
Pays : International
Références
Biochem Biophys Res Commun. 2000 Feb 5;268(1):2-7
pubmed: 10652202
J Cell Biochem. 2003 Sep 1;90(1):59-67
pubmed: 12938156
J Cell Biochem. 2018 Aug;119(8):6974-6985
pubmed: 29737562
Adv Exp Med Biol. 1990;274:271-93
pubmed: 2239428
Arthritis Rheum. 2000 Nov;43(11):2531-6
pubmed: 11083277
Arthritis Rheum. 1986 Aug;29(8):1039-49
pubmed: 3741515
Thorax. 2013 Jan;68(1):9-18
pubmed: 23051972
Mol Cell Endocrinol. 2001 Jun 30;180(1-2):163-7
pubmed: 11451587
Cytokine. 2008 Apr;42(1):85-91
pubmed: 18321725
Annu Rev Immunol. 1991;9:323-50
pubmed: 1910681
Mod Rheumatol. 2001 Jun;11(2):145-50
pubmed: 24383692
Mol Cell Endocrinol. 2012 Aug 15;359(1-2):101-6
pubmed: 22037168
Int J Inflam. 2014;2014:959271
pubmed: 25574420
Cell Cycle. 2010 Jun 15;9(12):2286-91
pubmed: 20519953
Adv Immunol. 2000;75:115-57
pubmed: 10879283
J Biol Chem. 2004 Oct 15;279(42):43514-21
pubmed: 15292256
Clin Exp Immunol. 1998 Apr;112(1):126-32
pubmed: 9566800
Nature. 1986 Jun 19-25;321(6072):776-9
pubmed: 3012369
Cell Mol Immunol. 2009 Apr;6(2):129-33
pubmed: 19403063
Cytokine. 1998 Mar;10(3):227-35
pubmed: 9576069
Br J Pharmacol. 1999 Jun;127(4):919-26
pubmed: 10433499
Am J Physiol Regul Integr Comp Physiol. 2012 Sep 15;303(6):R665-75
pubmed: 22855279
Am J Pathol. 1996 Nov;149(5):1607-15
pubmed: 8909250
Science. 1989 Dec 8;246(4935):1306-9
pubmed: 2479986
Arthritis Rheum. 1988 Mar;31(3):315-24
pubmed: 3358796
J Interferon Cytokine Res. 1998 Jul;18(7):491-8
pubmed: 9712365
Gene Ther. 2002 Nov;9(22):1508-19
pubmed: 12407423
J Endocrinol. 2004 Jul;182(1):69-80
pubmed: 15225132
Gastroenterology. 2005 Feb;128(2):411-23
pubmed: 15685552
Clin Exp Immunol. 2001 Oct;126(1):64-8
pubmed: 11678900
Clin Exp Allergy. 2006 Jul;36(7):941-50
pubmed: 16839410
Nature. 1986 Jun 19-25;321(6072):779-82
pubmed: 3086749
Nat Med. 2009 Dec;15(12):1414-20
pubmed: 19898488
Mol Cell Endocrinol. 1999 Feb 25;148(1-2):129-36
pubmed: 10221778
Arthritis Rheum. 2003 Sep;48(9):2442-9
pubmed: 13130463
Endocrinology. 2000 May;141(5):1905-8
pubmed: 10803603