Abstract
Follistatin-like protein 1 (FSTL1) is a secreted glycoprotein produced mainly by cells of mesenchymal origin. FSTL1 has been shown to play an important role during embryogenesis; FSTL1-deficient mice die at birth from multiple developmental abnormalities. In the last decade, FSTL1 has been identified as a novel inflammatory protein, enhancing synthesis of proinflammatory cytokines and chemokines by immune cells in vitro and in vivo. FSTL1 mediates proinflammatory events in animal models of inflammatory diseases, particularly in collagen-induced arthritis in mice. FSTL1 is elevated in various inflammatory conditions and decreased during the course of treatment. FSTL1 may therefore be a valuable biomarker for such diseases. Moreover, a variety of experiments suggest that targeting of FSTL1 may be useful in the treatment of diseases in which inflammation plays a central role.
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Shibanuma M, Mashimo J, Mita A, Kuroki T, Nose K. Cloning from a mouse osteoblastic cell line of a set of transforming-growth-factor-beta 1-regulated genes, one of which seems to encode a follistatin-related polypeptide. Eur J Biochem/FEBS. 1993;217(1):13–9.
Geng Y, Dong Y, Yu M, Zhang L, Yan X, Sun J, et al. Follistatin-like 1 (Fstl1) is a bone morphogenetic protein (BMP) 4 signaling antagonist in controlling mouse lung development. Proc Natl Acad Sci USA. 2011;108(17):7058–63. doi:10.1073/pnas.1007293108.
Sylva M, Li VS, Buffing AA, van Es JH, van den Born M, van der Velden S, et al. The BMP antagonist follistatin-like 1 is required for skeletal and lung organogenesis. PLoS One. 2011;6(8):e22616. doi:10.1371/journal.pone.0022616.
Tanaka M, Ozaki S, Osakada F, Mori K, Okubo M, Nakao K. Cloning of follistatin-related protein as a novel autoantigen in systemic rheumatic diseases. Int Immunol. 1998;10(9):1305–14.
Wilson DC, Marinov AD, Blair HC, Bushnell DS, Thompson SD, Chaly Y, et al. Follistatin-like protein 1 is a mesenchyme-derived inflammatory protein and may represent a biomarker for systemic-onset juvenile rheumatoid arthritis. Arthritis Rheum. 2010;62(8):2510–6. doi:10.1002/art.27485.
Chaly Y, Marinov AD, Oxburgh L, Bushnell DS, Hirsch R. FSTL1 promotes arthritis in mice by enhancing inflammatory cytokine/chemokine expression. Arthritis Rheum. 2012;64(4):1082–8. doi:10.1002/art.33422.
Keating A. Mesenchymal stromal cells: new directions. Cell Stem Cell. 2012;10(6):709–16. doi:10.1016/j.stem.2012.05.015.
Prockop DJ, Oh JY. Mesenchymal stem/stromal cells (MSCs): role as guardians of inflammation. Mol Ther. 2012;20(1):14–20. doi:10.1038/mt.2011.211.
Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell. 2013;13(4):392–402. doi:10.1016/j.stem.2013.09.006.
Oshima Y, Ouchi N, Sato K, Izumiya Y, Pimentel DR, Walsh K. Follistatin-like 1 is an Akt-regulated cardioprotective factor that is secreted by the heart. Circulation. 2008;117(24):3099–108. doi:10.1161/CIRCULATIONAHA.108.767673.
Liu S, Shen H, Xu M, Liu O, Zhao L, Liu S, et al. FRP inhibits ox-LDL-induced endothelial cell apoptosis through an Akt-NF-{kappa}B-Bcl-2 pathway and inhibits endothelial cell apoptosis in an apoE-knockout mouse model. Am J Physiol Endocrinol Metab. 2010;299(3):E351–63. doi:10.1152/ajpendo.00005.2010.
Ouchi N, Oshima Y, Ohashi K, Higuchi A, Ikegami C, Izumiya Y, et al. Follistatin-like 1, a secreted muscle protein, promotes endothelial cell function and revascularization in ischemic tissue through a nitric-oxide synthase-dependent mechanism. J Biol Chem. 2008;283(47):32802–11. doi:10.1074/jbc.M803440200.
Trojan L, Schaaf A, Steidler A, Haak M, Thalmann G, Knoll T, et al. Identification of metastasis-associated genes in prostate cancer by genetic profiling of human prostate cancer cell lines. Anticancer Res. 2005;25(1A):183–91.
Sundaram GM, Common JE, Gopal FE, Srikanta S, Lakshman K, Lunny DP, et al. ‘See-saw’ expression of microRNA-198 and FSTL1 from a single transcript in wound healing. Nature. 2013;495(7439):103–6. doi:10.1038/nature11890.
Chaly Y, Blair HC, Smith SM, Bushnell DS, Marinov AD, Campfield BT, et al. Follistatin-like protein 1 regulates chondrocyte proliferation and chondrogenic differentiation of mesenchymal stem cells. Ann Rheum Dis. 2014;. doi:10.1136/annrheumdis-2013-204822.
Hambrock HO, Kaufmann B, Muller S, Hanisch FG, Nose K, Paulsson M, et al. Structural characterization of TSC-36/Flik: analysis of two charge isoforms. J Biol Chem. 2004;279(12):11727–35. doi:10.1074/jbc.M309318200.
Zwijsen A, Blockx H, Van Arnhem W, Willems J, Fransen L, Devos K, et al. Characterization of a rat C6 glioma-secreted follistatin-related protein (FRP). Cloning and sequence of the human homologue. Eur J Biochem. 1994;225(3):937–46.
Murakami K, Tanaka M, Usui T, Kawabata D, Shiomi A, Iguchi-Hashimoto M, et al. Follistatin-related protein/follistatin-like 1 evokes an innate immune response via CD14 and toll-like receptor 4. FEBS Lett. 2012;586(4):319–24. doi:10.1016/j.febslet.2012.01.010.
Li L, Li X, Liu X, Dong Y, Geng Y, Liu X, et al. Expression, characterization, and preliminary X-ray crystallographic analysis of recombinant murine follistatin-like 1 expressed in Drosophila S2 cells. Biosci Trends. 2013;7(2):93–100.
Phillips DJ, de Kretser DM. Follistatin: a multifunctional regulatory protein. Front Neuroendocrinol. 1998;19(4):287–322. doi:10.1006/frne.1998.0169.
Phillips DJ, Jones KL, Clarke IJ, Scheerlinck JP, de Kretser DM. Activin A: from sometime reproductive factor to genuine cytokine. Vet Immunol Immunopathol. 2005;108(1–2):23–7. doi:10.1016/j.vetimm.2005.08.011.
Chang H, Brown CW, Matzuk MM. Genetic analysis of the mammalian transforming growth factor-beta superfamily. Endocr Rev. 2002;23(6):787–823. doi:10.1210/er.2002-0003.
Bamberger C, Scharer A, Antsiferova M, Tychsen B, Pankow S, Muller M, et al. Activin controls skin morphogenesis and wound repair predominantly via stromal cells and in a concentration-dependent manner via keratinocytes. Am J Pathol. 2005;167(3):733–47. doi:10.1016/S0002-9440(10)62047-0.
Mayer K, Buchbinder A, Morty RE. Activin A: a mediator governing inflammation, immunity, and repair. Am J Respir Crit Care Med. 2012;185(4):350–2. doi:10.1164/rccm.201112-2210ED.
Jones KL, Mansell A, Patella S, Scott BJ, Hedger MP, de Kretser DM, et al. Activin A is a critical component of the inflammatory response, and its binding protein, follistatin, reduces mortality in endotoxemia. Proc Natl Acad Sci USA. 2007;104(41):16239–44. doi:10.1073/pnas.0705971104.
Kawabata D, Tanaka M, Fujii T, Umehara H, Fujita Y, Yoshifuji H, et al. Ameliorative effects of follistatin-related protein/TSC-36/FSTL1 on joint inflammation in a mouse model of arthritis. Arthritis Rheum. 2004;50(2):660–8. doi:10.1002/art.20023.
Zhou J, Liao M, Hatta T, Tanaka M, Xuan X, Fujisaki K. Identification of a follistatin-related protein from the tick Haemaphysalis longicornis and its effect on tick oviposition. Gene. 2006;372:191–8. doi:10.1016/j.gene.2005.12.020.
Tanaka M, Murakami K, Ozaki S, Imura Y, Tong XP, Watanabe T, et al. DIP2 disco-interacting protein 2 homolog A (Drosophila) is a candidate receptor for follistatin-related protein/follistatin-like 1—analysis of their binding with TGF-beta superfamily proteins. FEBS J. 2010;277(20):4278–89. doi:10.1111/j.1742-4658.2010.07816.x.
Bork P. Shuffled domains in extracellular proteins. FEBS Lett. 1991;286(1–2):47–54.
Perkins SJ, Smith KF, Williams SC, Haris PI, Chapman D, Sim RB. The secondary structure of the von Willebrand factor type A domain in factor B of human complement by Fourier transform infrared spectroscopy. Its occurrence in collagen types VI, VII, XII and XIV, the integrins and other proteins by averaged structure predictions. J Mol Biol. 1994;238(1):104–19. doi:10.1006/jmbi.1994.1271.
Colombatti A, Bonaldo P, Doliana R. Type A modules: interacting domains found in several non-fibrillar collagens and in other extracellular matrix proteins. Matrix. 1993;13(4):297–306.
Tanaka M, Ozaki S, Kawabata D, Kishimura M, Osakada F, Okubo M, et al. Potential preventive effects of follistatin-related protein/TSC-36 on joint destruction and antagonistic modulation of its autoantibodies in rheumatoid arthritis. Int Immunol. 2003;15(1):71–7.
Le Luduec JB, Condamine T, Louvet C, Thebault P, Heslan JM, Heslan M, et al. An immunomodulatory role for follistatin-like 1 in heart allograft transplantation. Am J Transplant. 2008;8(11):2297–306. doi:10.1111/j.1600-6143.2008.02398.x.
Thornton S, Sowders D, Aronow B, Witte DP, Brunner HI, Giannini EH, et al. DNA microarray analysis reveals novel gene expression profiles in collagen-induced arthritis. Clin Immunol. 2002;105(2):155–68.
Clutter SD, Wilson DC, Marinov AD, Hirsch R. Follistatin-like protein 1 promotes arthritis by up-regulating IFN-gamma. J Immunol. 2009;182(1):234–9.
Ehara Y, Sakurai D, Tsuchiya N, Nakano K, Tanaka Y, Yamaguchi A, et al. Follistatin-related protein gene (FRP) is expressed in the synovial tissues of rheumatoid arthritis, but its polymorphisms are not associated with genetic susceptibility. Clin Exp Rheumatol. 2004;22(6):707–12.
Li D, Wang Y, Xu N, Wei Q, Wu M, Li X, et al. Follistatin-like protein 1 is elevated in systemic autoimmune diseases and correlated with disease activity in patients with rheumatoid arthritis. Arthritis Res Ther. 2011;13(1):R17. doi:10.1186/ar3241.
Gorelik M, Fall N, Altaye M, Barnes MG, Thompson SD, Grom AA, et al. Follistatin-like protein 1 and the ferritin/erythrocyte sedimentation rate ratio are potential biomarkers for dysregulated gene expression and macrophage activation syndrome in systemic juvenile idiopathic arthritis. J Rheumatol. 2013;40(7):1191–9. doi:10.3899/jrheum.121131.
Widera C, Horn-Wichmann R, Kempf T, Bethmann K, Fiedler B, Sharma S, et al. Circulating concentrations of follistatin-like 1 in healthy individuals and patients with acute coronary syndrome as assessed by an immunoluminometric sandwich assay. Clin Chem. 2009;55(10):1794–800. doi:10.1373/clinchem.2009.129411.
Gorelik M, Wilson DC, Cloonan YK, Shulman ST, Hirsch R. Plasma follistatin-like protein 1 is elevated in Kawasaki disease and may predict coronary artery aneurysm formation. J Pediatr. 2012;161(1):116–9. doi:10.1016/j.jpeds.2012.01.011.
Chaly Y, Fu Y, Marinov A, Hostager B, Yan W, Campfield B, et al. Follistatin-like protein 1 enhances NLRP3 inflammasome-mediated IL-1beta secretion from monocytes and macrophages. Eur J Immunol. 2014;. doi:10.1002/eji.201344063.
Hoffman HM. Therapy of autoinflammatory syndromes. J Allergy Clin Immunol. 2009;124(6):1129–38. doi:10.1016/j.jaci.2009.11.001 (quiz 39–40).
Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome. Nat Genet. 2001;29(3):301–5. doi:10.1038/ng756.
Gorelik M, Bushnell D, Goldbach-Mansky RT, Hoffman HM, Hirsch R. Elevated serum follistatin-like protein 1 suggests an interleukin-1 independent pathway for inflammation in patients with cryopyrin associated periodic syndromes. Arthritis Rheum. 2012;64(10):S1125–6.
Fan N, Sun H, Wang Y, Wang Y, Zhang L, Xia Z, et al. Follistatin-like 1: a potential mediator of inflammation in obesity. Mediators Inflamm. 2013;2013:752519. doi:10.1155/2013/752519.
Li KC, Zhang FX, Li CL, Wang F, Yu MY, Zhong YQ, et al. Follistatin-like 1 suppresses sensory afferent transmission by activating Na + , K + -ATPase. Neuron. 2011;69(5):974–87. doi:10.1016/j.neuron.2011.01.022.
Miyamae T, Marinov AD, Sowders D, Wilson DC, Devlin J, Boudreau R, et al. Follistatin-like protein-1 is a novel proinflammatory molecule. J Immunol. 2006;177(7):4758–62.
Bouffi C, Djouad F, Mathieu M, Noel D, Jorgensen C. Multipotent mesenchymal stromal cells and rheumatoid arthritis: risk or benefit? Rheumatology. 2009;48(10):1185–9. doi:10.1093/rheumatology/kep162.
Ouchi N, Asaumi Y, Ohashi K, Higuchi A, Sono-Romanelli S, Oshima Y, et al. DIP2A functions as a FSTL1 receptor. J Biol Chem. 2010;285(10):7127–34. doi:10.1074/jbc.M109.069468.
Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol. 2009;183(2):787–91. doi:10.4049/jimmunol.0901363.
Shimano M, Ouchi N, Nakamura K, van Wijk B, Ohashi K, Asaumi Y, et al. Cardiac myocyte follistatin-like 1 functions to attenuate hypertrophy following pressure overload. Proc Natl Acad Sci USA. 2011;108(43):E899–906. doi:10.1073/pnas.1108559108.
Acknowledgments
This work was supported by National Institute of Health Grants RO1 AI073556 and RO1 AR056959 (to R. H.).
Conflict of interest
The University of Pittsburgh has a patent for the use of FSTL1 as a disease target listing R. Hirsch as an inventor.
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Chaly, Y., Hostager, B., Smith, S. et al. Follistatin-like protein 1 and its role in inflammation and inflammatory diseases. Immunol Res 59, 266–272 (2014). https://doi.org/10.1007/s12026-014-8526-z
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DOI: https://doi.org/10.1007/s12026-014-8526-z