Skip to main content
Top
Published in: Japanese Journal of Ophthalmology 1/2021

01-01-2021 | Laboratory Investigation

Role of oncostatin M in the pathogenesis of vernal keratoconjunctivitis: focus on tissue remodeling

Authors: Keitaro Mashimo, Ayumi Usui-Ouchi, Yousuke Ito, Rei Wakasa-Arai, Norihiko Yokoi, Satoshi Kawasaki, Akira Murakami, Akira Matsuda, Nobuyuki Ebihara

Published in: Japanese Journal of Ophthalmology | Issue 1/2021

Login to get access

Abstract

Purpose

Vernal keratoconjunctivitis (VKC) is a severe and recurrent allergic conjunctivitis, the mechanism of which is not well understood. In this study, we investigated the role of oncostatin M (OSM) in the pathogenesis of VKC, with a focus on tissue remodeling.

Study design

Clinical and experimental.

Patients and methods

The OSM concentrations in tear fluid samples obtained from VKC patients and healthy controls were measured using ELISA, and the expression of OSM mRNA and protein in giant papillae resected from VKC patients was investigated using RT-PCR and immunohistochemistry, respectively. In cultured human conjunctival epithelial cells (HconEpiCs), expression of OSM receptor β (OSMRβ) was detected using immunocytochemical and FACS analyses. Finally, we investigated whether recombinant OSM activated STAT1 and STAT3 to induce the expression of various genes related to tissue remodeling in HconEpiCs, by using Western blot analysis, microarray analysis, and RT-PCR.

Results

The OSM concentration was higher in the tear fluid of VKC patients than in that of the healthy controls, and strong expression of OSM mRNA was found in the giant papillae. We also detected T cells expressing OSM in the giant papillae. In addition, HconEpiCs showed surface expression of OSMRβ. Recombinant human OSM strongly activated both STAT1 and STAT3 in HconEpiCs and induced various tissue remodeling-related genes, including MMP-1, MMP-3, IL-24, IL-20, serpinB3, S100A7, tenascin C, and SOCS3.

Conclusion

Our results suggest that OSM is one of the key molecules involved in remodeling of giant papillae in VKC.
Literature
1.
go back to reference Tanaka M, Miyajima A. Oncostatin M: a multifunctional cytokine. Rev Physiol Biochem Pharmacol. 2003;149:39–52.PubMedCrossRef Tanaka M, Miyajima A. Oncostatin M: a multifunctional cytokine. Rev Physiol Biochem Pharmacol. 2003;149:39–52.PubMedCrossRef
2.
go back to reference Jones SA, Jenkins BJ. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat Rev Immunol. 2018;18:773–89.PubMedCrossRef Jones SA, Jenkins BJ. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat Rev Immunol. 2018;18:773–89.PubMedCrossRef
3.
go back to reference Boniface K, Diveu C, Morel F, Pedretti N, Froger J, Ravon E, et al. Oncostatin M secreted by skin infiltrating T lymphocytes is a potent keratinocyte activator involved in skin inflammation. J Immunol. 2007;178:4615–22.PubMedCrossRef Boniface K, Diveu C, Morel F, Pedretti N, Froger J, Ravon E, et al. Oncostatin M secreted by skin infiltrating T lymphocytes is a potent keratinocyte activator involved in skin inflammation. J Immunol. 2007;178:4615–22.PubMedCrossRef
4.
go back to reference Fritz DK, Kerr C, Fattouh R, Llop-Guevara A, Khan WI, Jordana M, et al. A mouse model of airway disease: oncostatin M-induced pulmonary eosinophilia, goblet cell hyperplasia, and airway hyperresponsiveness are STAT6 dependent, and interstitial pulmonary fibrosis is STAT6 independent. J Immunol. 2011;186:1107–18.PubMedCrossRef Fritz DK, Kerr C, Fattouh R, Llop-Guevara A, Khan WI, Jordana M, et al. A mouse model of airway disease: oncostatin M-induced pulmonary eosinophilia, goblet cell hyperplasia, and airway hyperresponsiveness are STAT6 dependent, and interstitial pulmonary fibrosis is STAT6 independent. J Immunol. 2011;186:1107–18.PubMedCrossRef
5.
go back to reference Nagahama KY, Togo S, Holz O, Magnussen H, Liu X, Seyama K, et al. Oncostatin M modulates fibroblast function via signal transducers and activators of transcription proteins-3. Am J Respir Cell Mol Biol. 2013;49:582–91.PubMedCrossRef Nagahama KY, Togo S, Holz O, Magnussen H, Liu X, Seyama K, et al. Oncostatin M modulates fibroblast function via signal transducers and activators of transcription proteins-3. Am J Respir Cell Mol Biol. 2013;49:582–91.PubMedCrossRef
6.
go back to reference Kang HJ, Kang JS, Lee SH, Hwang SJ, Chae SW, Woo JS, et al. Upregulation of oncostatin M in allergic rhinitis. Laryngoscope. 2005;115:2213–6.PubMedCrossRef Kang HJ, Kang JS, Lee SH, Hwang SJ, Chae SW, Woo JS, et al. Upregulation of oncostatin M in allergic rhinitis. Laryngoscope. 2005;115:2213–6.PubMedCrossRef
7.
go back to reference Mozaffarian A, Brewer AW, Trueblood ES, Luzina IG, Todd NW, Atamas SP, et al. Mechanisms of oncostatin M-induced pulmonary inflammation and fibrosis. J Immunol. 2008;181:7243–53.PubMedCrossRef Mozaffarian A, Brewer AW, Trueblood ES, Luzina IG, Todd NW, Atamas SP, et al. Mechanisms of oncostatin M-induced pulmonary inflammation and fibrosis. J Immunol. 2008;181:7243–53.PubMedCrossRef
8.
go back to reference Johnson RB. Use of NSAIDs in long-distance runners: a risk factor for sudden death? South Med J. 1989;82:95.PubMedCrossRef Johnson RB. Use of NSAIDs in long-distance runners: a risk factor for sudden death? South Med J. 1989;82:95.PubMedCrossRef
9.
go back to reference Scaffidi AK, Mutsaers SE, Moodley YP, McAnulty RJ, Laurent GJ, Thompson PJ, et al. Oncostatin M stimulates proliferation, induces collagen production and inhibits apoptosis of human lung fibroblasts. Br J Pharmacol. 2002;136:793–801.PubMedPubMedCentralCrossRef Scaffidi AK, Mutsaers SE, Moodley YP, McAnulty RJ, Laurent GJ, Thompson PJ, et al. Oncostatin M stimulates proliferation, induces collagen production and inhibits apoptosis of human lung fibroblasts. Br J Pharmacol. 2002;136:793–801.PubMedPubMedCentralCrossRef
10.
go back to reference Duncan MR, Hasan A, Berman B. Oncostatin M stimulates collagen and glycosaminoglycan production by cultured normal dermal fibroblasts: insensitivity of sclerodermal and keloidal fibroblasts. J Invest Dermatol. 1995;104:128–33.PubMedCrossRef Duncan MR, Hasan A, Berman B. Oncostatin M stimulates collagen and glycosaminoglycan production by cultured normal dermal fibroblasts: insensitivity of sclerodermal and keloidal fibroblasts. J Invest Dermatol. 1995;104:128–33.PubMedCrossRef
11.
go back to reference Bamber B, Reife RA, Haugen HS, Clegg CH. Oncostatin M stimulates excessive extracellular matrix accumulation in a transgenic mouse model of connective tissue disease. J Mol Med (Berl). 1998;76:61–9.CrossRef Bamber B, Reife RA, Haugen HS, Clegg CH. Oncostatin M stimulates excessive extracellular matrix accumulation in a transgenic mouse model of connective tissue disease. J Mol Med (Berl). 1998;76:61–9.CrossRef
12.
go back to reference Wong S, Botelho FM, Rodrigues RM, Richards CD. Oncostatin M overexpression induces matrix deposition, STAT3 activation, and SMAD1 Dysregulation in lungs of fibrosis-resistant BALB/c mice. Lab Invest. 2014;94:1003–16.PubMedCrossRef Wong S, Botelho FM, Rodrigues RM, Richards CD. Oncostatin M overexpression induces matrix deposition, STAT3 activation, and SMAD1 Dysregulation in lungs of fibrosis-resistant BALB/c mice. Lab Invest. 2014;94:1003–16.PubMedCrossRef
13.
go back to reference Sarkozi R, Hauser C, Noppert SJ, Kronbichler A, Pirklbauer M, Haller VM, et al. Oncostatin M is a novel inhibitor of TGF-beta1-induced matricellular protein expression. Am J Physiol Renal Physiol. 2011;301:F1014–25.PubMedCrossRef Sarkozi R, Hauser C, Noppert SJ, Kronbichler A, Pirklbauer M, Haller VM, et al. Oncostatin M is a novel inhibitor of TGF-beta1-induced matricellular protein expression. Am J Physiol Renal Physiol. 2011;301:F1014–25.PubMedCrossRef
14.
go back to reference Abe H, Takeda N, Isagawa T, Semba H, Nishimura S, Morioka MS, et al. Macrophage hypoxia signaling regulates cardiac fibrosis via Oncostatin M. Nat Commun. 2019;10:2824.PubMedPubMedCentralCrossRef Abe H, Takeda N, Isagawa T, Semba H, Nishimura S, Morioka MS, et al. Macrophage hypoxia signaling regulates cardiac fibrosis via Oncostatin M. Nat Commun. 2019;10:2824.PubMedPubMedCentralCrossRef
15.
go back to reference Huguier V, Giot JP, Simonneau M, Levillain P, Charreau S, Garcia M, et al. Oncostatin M exerts a protective effect against excessive scarring by counteracting the inductive effect of TGFbeta1 on fibrosis markers. Sci Rep. 2019;9:2113.PubMedPubMedCentralCrossRef Huguier V, Giot JP, Simonneau M, Levillain P, Charreau S, Garcia M, et al. Oncostatin M exerts a protective effect against excessive scarring by counteracting the inductive effect of TGFbeta1 on fibrosis markers. Sci Rep. 2019;9:2113.PubMedPubMedCentralCrossRef
16.
go back to reference Iwamoto S, Asada Y, Ebihara N, Hori K, Okayama Y, Kashiwakura J, et al. Interaction between conjunctival epithelial cells and mast cells induces CCL2 expression and piecemeal degranulation in mast cells. Invest Ophthalmol Vis Sci. 2013;54:2465–73.PubMedCrossRef Iwamoto S, Asada Y, Ebihara N, Hori K, Okayama Y, Kashiwakura J, et al. Interaction between conjunctival epithelial cells and mast cells induces CCL2 expression and piecemeal degranulation in mast cells. Invest Ophthalmol Vis Sci. 2013;54:2465–73.PubMedCrossRef
17.
go back to reference Tanioka H, Kawasaki S, Yamasaki K, Ang LP, Koizumi N, Nakamura T, et al. Establishment of a cultivated human conjunctival epithelium as an alternative tissue source for autologous corneal epithelial transplantation. Invest Ophthalmol Vis Sci. 2006;47:3820–7.PubMedCrossRef Tanioka H, Kawasaki S, Yamasaki K, Ang LP, Koizumi N, Nakamura T, et al. Establishment of a cultivated human conjunctival epithelium as an alternative tissue source for autologous corneal epithelial transplantation. Invest Ophthalmol Vis Sci. 2006;47:3820–7.PubMedCrossRef
18.
go back to reference Ang LP, Tanioka H, Kawasaki S, Ang LP, Yamasaki K, Do TP, et al. Cultivated human conjunctival epithelial transplantation for total limbal stem cell deficiency. Invest Ophthalmol Vis Sci. 2010;51:758–64.PubMedCrossRef Ang LP, Tanioka H, Kawasaki S, Ang LP, Yamasaki K, Do TP, et al. Cultivated human conjunctival epithelial transplantation for total limbal stem cell deficiency. Invest Ophthalmol Vis Sci. 2010;51:758–64.PubMedCrossRef
19.
go back to reference Kinoshita S, Kawasaki S, Kitazawa K, Shinomiya K. Establishment of a human conjunctival epithelial cell line lacking the functional TACSTD2 gene (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc. 2012;110:166–77.PubMedPubMedCentral Kinoshita S, Kawasaki S, Kitazawa K, Shinomiya K. Establishment of a human conjunctival epithelial cell line lacking the functional TACSTD2 gene (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc. 2012;110:166–77.PubMedPubMedCentral
20.
go back to reference Matsuda A, Ebihara N, Yokoi N, Kawasaki S, Tanioka H, Inatomi T, et al. Functional role of thymic stromal lymphopoietin in chronic allergic keratoconjunctivitis. Invest Ophthalmol Vis Sci. 2010;51:151–5.PubMedCrossRef Matsuda A, Ebihara N, Yokoi N, Kawasaki S, Tanioka H, Inatomi T, et al. Functional role of thymic stromal lymphopoietin in chronic allergic keratoconjunctivitis. Invest Ophthalmol Vis Sci. 2010;51:151–5.PubMedCrossRef
21.
go back to reference Pothoven KL, Norton JE, Suh LA, Carter RG, Harris KE, Biyasheva A, et al. Neutrophils are a major source of the epithelial barrier disrupting cytokine oncostatin M in patients with mucosal airways disease. J Allergy Clin Immunol. 2017;139:1966–78.PubMedCrossRef Pothoven KL, Norton JE, Suh LA, Carter RG, Harris KE, Biyasheva A, et al. Neutrophils are a major source of the epithelial barrier disrupting cytokine oncostatin M in patients with mucosal airways disease. J Allergy Clin Immunol. 2017;139:1966–78.PubMedCrossRef
22.
go back to reference Suda T, Chida K, Todate A, Ide K, Asada K, Nakamura Y, et al. Oncostatin M production by human dendritic cells in response to bacterial products. Cytokine. 2002;17:335–40.PubMedCrossRef Suda T, Chida K, Todate A, Ide K, Asada K, Nakamura Y, et al. Oncostatin M production by human dendritic cells in response to bacterial products. Cytokine. 2002;17:335–40.PubMedCrossRef
23.
go back to reference Salamon P, Shoham NG, Puxeddu I, Paitan Y, Levi-Schaffer F, Mekori YA. Human mast cells release oncostatin M on contact with activated T cells: possible biologic relevance. J Allergy Clin Immunol. 2008;121:448–55.PubMedCrossRef Salamon P, Shoham NG, Puxeddu I, Paitan Y, Levi-Schaffer F, Mekori YA. Human mast cells release oncostatin M on contact with activated T cells: possible biologic relevance. J Allergy Clin Immunol. 2008;121:448–55.PubMedCrossRef
24.
go back to reference Grenier A, Dehoux M, Boutten A, Arce-Vicioso M, Durand G, Gougerot-Pocidalo MA, et al. Oncostatin M production and regulation by human polymorphonuclear neutrophils. Blood. 1999;93:1413–21.PubMedCrossRef Grenier A, Dehoux M, Boutten A, Arce-Vicioso M, Durand G, Gougerot-Pocidalo MA, et al. Oncostatin M production and regulation by human polymorphonuclear neutrophils. Blood. 1999;93:1413–21.PubMedCrossRef
25.
go back to reference Uriarte SM, Powell DW, Luerman GC, Merchant ML, Cummins TD, Jog NR, et al. Comparison of proteins expressed on secretory vesicle membranes and plasma membranes of human neutrophils. J Immunol. 2008;180:5575–81.PubMedCrossRef Uriarte SM, Powell DW, Luerman GC, Merchant ML, Cummins TD, Jog NR, et al. Comparison of proteins expressed on secretory vesicle membranes and plasma membranes of human neutrophils. J Immunol. 2008;180:5575–81.PubMedCrossRef
26.
go back to reference Young D, Das N, Anowai A, Dufour A. Matrix metalloproteases as influencers of the cells’ social media. Int J Mol Sci. 2019;20:3847.PubMedCentralCrossRef Young D, Das N, Anowai A, Dufour A. Matrix metalloproteases as influencers of the cells’ social media. Int J Mol Sci. 2019;20:3847.PubMedCentralCrossRef
27.
go back to reference Ryan RE, Martin B, Mellor L, Jacob RB, Tawara K, McDougal OM, et al. Oncostatin M binds to extracellular matrix in a bioactive conformation: implications for inflammation and metastasis. Cytokine. 2015;72:71–85.PubMedPubMedCentralCrossRef Ryan RE, Martin B, Mellor L, Jacob RB, Tawara K, McDougal OM, et al. Oncostatin M binds to extracellular matrix in a bioactive conformation: implications for inflammation and metastasis. Cytokine. 2015;72:71–85.PubMedPubMedCentralCrossRef
28.
go back to reference Leonardi A, Brun P, Abatangelo G, Plebani M, Secchi AG. Tear levels and activity of matrix metalloproteinase (MMP)-1 and MMP-9 in vernal keratoconjunctivitis. Invest Ophthalmol Vis Sci. 2003;44:3052–8.PubMedCrossRef Leonardi A, Brun P, Abatangelo G, Plebani M, Secchi AG. Tear levels and activity of matrix metalloproteinase (MMP)-1 and MMP-9 in vernal keratoconjunctivitis. Invest Ophthalmol Vis Sci. 2003;44:3052–8.PubMedCrossRef
29.
go back to reference Turato C, Pontisso P. SERPINB3 (serpin peptidase inhibitor, clade B (ovalbumin), member 3). Atlas Genet Cytogenet Oncol Haematol. 2015;19:202–9.PubMedPubMedCentral Turato C, Pontisso P. SERPINB3 (serpin peptidase inhibitor, clade B (ovalbumin), member 3). Atlas Genet Cytogenet Oncol Haematol. 2015;19:202–9.PubMedPubMedCentral
31.
go back to reference Pothoven KL, Norton JE, Hulse KE, Suh LA, Carter RG, Rocci E, et al. Oncostatin M promotes mucosal epithelial barrier dysfunction, and its expression is increased in patients with eosinophilic mucosal disease. J Allergy Clin Immunol. 2015;136(737–46):e4. Pothoven KL, Norton JE, Hulse KE, Suh LA, Carter RG, Rocci E, et al. Oncostatin M promotes mucosal epithelial barrier dysfunction, and its expression is increased in patients with eosinophilic mucosal disease. J Allergy Clin Immunol. 2015;136(737–46):e4.
32.
go back to reference Pothoven KL, Schleimer RP. The barrier hypothesis and Oncostatin M: restoration of epithelial barrier function as a novel therapeutic strategy for the treatment of type 2 inflammatory disease. Tissue Barriers. 2017;5:e1341367.PubMedPubMedCentralCrossRef Pothoven KL, Schleimer RP. The barrier hypothesis and Oncostatin M: restoration of epithelial barrier function as a novel therapeutic strategy for the treatment of type 2 inflammatory disease. Tissue Barriers. 2017;5:e1341367.PubMedPubMedCentralCrossRef
33.
go back to reference Rutz S, Wang X, Ouyang W. The IL-20 subfamily of cytokines: from host defence to tissue homeostasis. Nat Rev Immunol. 2014;14:783–95.PubMedCrossRef Rutz S, Wang X, Ouyang W. The IL-20 subfamily of cytokines: from host defence to tissue homeostasis. Nat Rev Immunol. 2014;14:783–95.PubMedCrossRef
34.
go back to reference Tohyama M, Hanakawa Y, Shirakata Y, Dai X, Yang L, Hirakawa S, et al. IL-17 and IL-22 mediate IL-20 subfamily cytokine production in cultured keratinocytes via increased IL-22 receptor expression. Eur J Immunol. 2009;39:2779–88.PubMedCrossRef Tohyama M, Hanakawa Y, Shirakata Y, Dai X, Yang L, Hirakawa S, et al. IL-17 and IL-22 mediate IL-20 subfamily cytokine production in cultured keratinocytes via increased IL-22 receptor expression. Eur J Immunol. 2009;39:2779–88.PubMedCrossRef
35.
go back to reference Madsen P, Rasmussen HH, Leffers H, Honore B, Dejgaard K, Olsen E, et al. Molecular cloning, occurrence, and expression of a novel partially secreted protein “psoriasin” that is highly up-regulated in psoriatic skin. J Invest Dermatol. 1991;97:701–12.PubMedCrossRef Madsen P, Rasmussen HH, Leffers H, Honore B, Dejgaard K, Olsen E, et al. Molecular cloning, occurrence, and expression of a novel partially secreted protein “psoriasin” that is highly up-regulated in psoriatic skin. J Invest Dermatol. 1991;97:701–12.PubMedCrossRef
36.
go back to reference Hoffmann HJ, Olsen E, Etzerodt M, Madsen P, Thogersen HC, Kruse T, et al. Psoriasin binds calcium and is upregulated by calcium to levels that resemble those observed in normal skin. J Invest Dermatol. 1994;103:370–5.PubMedCrossRef Hoffmann HJ, Olsen E, Etzerodt M, Madsen P, Thogersen HC, Kruse T, et al. Psoriasin binds calcium and is upregulated by calcium to levels that resemble those observed in normal skin. J Invest Dermatol. 1994;103:370–5.PubMedCrossRef
37.
38.
go back to reference Ostergaard M, Wolf H, Orntoft TF, Celis JE. Psoriasin (S100A7): a putative urinary marker for the follow-up of patients with bladder squamous cell carcinomas. Electrophoresis. 1999;20:349–54.PubMedCrossRef Ostergaard M, Wolf H, Orntoft TF, Celis JE. Psoriasin (S100A7): a putative urinary marker for the follow-up of patients with bladder squamous cell carcinomas. Electrophoresis. 1999;20:349–54.PubMedCrossRef
39.
go back to reference Vegfors J, Ekman AK, Stoll SW, Bivik Eding C, Enerback C. Psoriasin (S100A7) promotes stress-induced angiogenesis. Br J Dermatol. 2016;175:1263–73.PubMedCrossRef Vegfors J, Ekman AK, Stoll SW, Bivik Eding C, Enerback C. Psoriasin (S100A7) promotes stress-induced angiogenesis. Br J Dermatol. 2016;175:1263–73.PubMedCrossRef
40.
41.
42.
go back to reference Ohtomo K, Ebihara N, Matsuda A, Tokura T, Funaki T, Murakami A. Role of TGF-beta in tissue eosinophilia associated with vernal keratoconjunctivitis. Exp Eye Res. 2010;91:748–54.PubMedCrossRef Ohtomo K, Ebihara N, Matsuda A, Tokura T, Funaki T, Murakami A. Role of TGF-beta in tissue eosinophilia associated with vernal keratoconjunctivitis. Exp Eye Res. 2010;91:748–54.PubMedCrossRef
Metadata
Title
Role of oncostatin M in the pathogenesis of vernal keratoconjunctivitis: focus on tissue remodeling
Authors
Keitaro Mashimo
Ayumi Usui-Ouchi
Yousuke Ito
Rei Wakasa-Arai
Norihiko Yokoi
Satoshi Kawasaki
Akira Murakami
Akira Matsuda
Nobuyuki Ebihara
Publication date
01-01-2021
Publisher
Springer Japan
Published in
Japanese Journal of Ophthalmology / Issue 1/2021
Print ISSN: 0021-5155
Electronic ISSN: 1613-2246
DOI
https://doi.org/10.1007/s10384-020-00791-8

Other articles of this Issue 1/2021

Japanese Journal of Ophthalmology 1/2021 Go to the issue