Interferon-γ Induces Interleukin-6 Production and Alpha-smooth Muscle Actin Expression in Systemic Sclerosis Fibroblasts
-
Mohsen Rokni
,
Elham Farhadi
,
Hoda Kavosi
,
Maryam Akhtari
,
Elham Madreseh
,
Samaneh Enayati
,
Mina Sadeghi Shaker
,
Shayan Mostafaei
,
Farhad Gharibdoost
,
Mahdi Mahmoudi
,
Mohammad Vodjgani
Abstract
Systemic sclerosis (SSc) is an autoimmune systemic disease that is characterized by immune dysregulation, inflammation, vasculopathy, and fibrosis. Tissue fibrosis plays an important role in SSc and can affect several organs such as the dermis, lungs, and heart. Dysregulation of interferon (IFN) signaling contributes to the SSc pathogenesis and interferon regulatory factor 1 (IRF1) has been indicated as the main regulator of type I IFN.
This study aimed to clarify the effect of IFN-gamma (-γ) and dexamethasone (DEX) on the IRF1, extracellular signal-regulated kinase 1/2 (ERK1/2), and the expression of alpha-smooth muscle actin (α-SMA) in myofibroblasts and genes involved in the inflammation and fibrosis processes in early diffuse cutaneous systemic sclerosis (dcSSc). A total of 10 early dcSSc patients (diffuse cutaneous form) and 10 unaffected control dermis biopsies were obtained to determine IFNγ and DEX effects on inflammation and fibrosis. Fibroblasts were treated with IFNγ and DEX at optimum time and dose. The expression level of genes and proteins involved in the fibrosis and inflammation processes have been quantified by quantitative real-time PCR (RT-qPCR) and western blot, respectively.
IFNγ could up-regulate some of the inflammation-related genes (Interleukin-6; IL6) and down-regulate some of the fibrosis-related genes (COL1A1) in cultured fibroblasts of patients with early dcSSc compared to the untreated group. Besides, it has been revealed that IFNγ can induce fibroblast differentiation to the myofibroblast that expresses α-SMA.
Concerning the inhibitory effect of IFNγ on some fibrotic genes and its positive effect on the inflammatory genes and myofibroblast differentiation, it seems that IFNγ may play a dual role in SSc.
1. Rokni M, Sadeghi Shaker M, Kavosi H, Shokoofi S, Mahmoudi M, Farhadi E. The role of endothelin and RAS/ERK signaling in immunopathogenesis-related fibrosis in patients with systemic sclerosis: an updated review with therapeutic implications. Arthritis Res Ther. 2022;24(1):1-13.
2. Sadeghi Shaker M, Rokni M, Mahmoudi M, Farhadi E. Ras family signaling pathway in immunopathogenesis of inflammatory rheumatic diseases. Front Immunol. 2023;14. English.
3. Ototake Y, Yamaguchi Y, Asami M, Komitsu N, Akita A, Watanabe T, et al. Downregulated IRF8 in monocytes and macrophages of patients with systemic sclerosis may aggravate the fibrotic phenotype. J Invest Dermatol. 2021;141(8):1954-63.
4. Skaug B, Assassi S. Type I interferon dysregulation in Systemic Sclerosis. Cytokine. 2020;132:154635.
5. Wu M, Assassi S. The role of type 1 interferon in systemic sclerosis. Front Immunol. 20136;4:266.
6. Gonçalves RSG, Pereira MC, Dantas AT, Almeida AR, Rego M, Lima EA, et al. CCL3, IL-7, IL-13 and IFNγ transcripts are increased in skin's biopsy of systemic sclerosis. Exp Dermatol. 2019;28(10):1172-5.
7. Wang WM, Li F, Jin HZ. Role of interferon regulatory factor-mediated signaling in psoriasis. Int J Med Sci. 2021;18(16):3794-9.
8. Wu M, Skaug B, Bi X, Mills T, Salazar G, Zhou X, et al. Interferon regulatory factor 7 (IRF7) represents a link between inflammation and fibrosis in the pathogenesis of systemic sclerosis. Ann Rheum Dis. 2019;78(11):1583-91.
9. Wu M, Salazar G, Ying J, Charles J, Zhou X, Mayes MD, et al., editors. Interferon Regulatory Factor (IRF) 7 in Type I IFN Signaling Represents As a Key Upstream Regulator in Early Diffuse SSc Patients and Plays Critical Role in Pathogenesis of Fibrosis. Arthritis Rheumatol; 2017: WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ USA.
10. Li Y, Liu Y, Huang Y, Yang K, Xiao T, Xiong J, et al. IRF‐1 promotes renal fibrosis by downregulation of Klotho. FASEB J. 2020;34(3):4415-29.
11. González-Serna D, Ochoa E, López-Isac E, Julià A, Degenhardt F, Ortego-Centeno N, et al. A cross-disease meta-GWAS identifies four new susceptibility loci shared between systemic sclerosis and Crohn's disease. Sci Rep. 2020;10(1):1862.
12. Zeng Z, Wang Y, Xiao Y, Zheng J, Liu R, He X, et al. Overexpression of OASL upregulates TET1 to induce aberrant activation of CD4(+) T cells in systemic sclerosis via IRF1 signaling. Arthritis Res Ther. 2022;24(1):50.
13. Li Y, Zhao J, Yin Y, Li K, Zhang C, Zheng Y. The Role of IL-6 in Fibrotic Diseases: Molecular and Cellular Mechanisms. Int J Biol Sci. 2022;18(14):5405-14.
14. Khan K, Xu S, Nihtyanova S, Derrett-Smith E, Abraham D, Denton CP, et al. Clinical and pathological significance of interleukin 6 overexpression in systemic sclerosis. Ann Rheum Dis. 2012;71(7):1235-42.
15. Van Den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheumatol. 2013;65(11):2737-47.
16. Medsger Jr T. Systemic sclerosis (scleroderma) localized scleroderma, eosinophilic fasciitis, and calcinosis. Arthritis and allied conditions. 1993:1118-65.
17. Hungness ES, Luo GJ, Pritts TA, Sun X, Robb BW, Hershko D, et al. Transcription factors C/EBP-beta and -delta regulate IL-6 production in IL-1beta-stimulated human enterocytes. J Cell Physiol. 2002;192(1):64-70.
18. Dogra D, Dogra N, Gupta G, Mushtaq S. Dexamethasone-cyclophosphamide pulse therapy in systemic sclerosis: A retrospective study from a tertiary care hospital. Indian J Dermatol Venereol Leprol. 2017;83:494.
19. Han S, Bui NT, Ho MT, Kim YM, Cho M, Shin DB. Dexamethasone Inhibits TGF-β1-Induced Cell Migration by Regulating the ERK and AKT Pathways in Human Colon Cancer Cells Via CYR61. Cancer Res Treat. 2016;48(3):1141-53.
20. Iudici M, Vettori S, Russo B, Giacco V, Capocotta D, Valentini G. Outcome of a glucocorticoid discontinuation regimen in patients with inactive systemic sclerosis. Clin Rheumatol. 2016;35(8):1985-91.
21. de Almeida AR, Dantas AT, Pereira MC, Cordeiro MF, Gonçalves RSG, de Melo Rêgo MJB, et al. Dexamethasone inhibits cytokine production in PBMC from systemic sclerosis patients. Inflammopharmacology. 2019;27(4):723-30.
22. Wang W, Xia X, Mao L, Wang S. The CCAAT/Enhancer-Binding Protein Family: Its Roles in MDSC Expansion and Function. Front Immunol. 2019;10.
23. Nunez BS, Geng CD, Pedersen KB, Millro-Macklin CD, Vedeckis WV. Interaction between the interferon signaling pathway and the human glucocorticoid receptor gene 1A promoter. Endocrinology. 2005;146(3):1449-57.
24. Yuan W, Yufit T, Li L, Mori Y, Chen SJ, Varga J. Negative modulation of α1 (I) procollagen gene expression in human skin fibroblasts: Transcriptional inhibition by interferon‐γ. J Cell Physiol. 1999;179(1):97-108.
25. Flammer JR, Dobrovolna J, Kennedy MA, Chinenov Y, Glass CK, Ivashkiv LB, et al. The type I interferon signaling pathway is a target for glucocorticoid inhibition. Mol Cell Biol. 2010;30(19):4564-74.
26. Barnes TC, Anderson ME, Moots RJ. The many faces of interleukin-6: the role of IL-6 in inflammation, vasculopathy, and fibrosis in systemic sclerosis. Int J Rheumatol. 2011;2011:721608.
27. Porée B, Kypriotou M, Chadjichristos C, Beauchef G, Renard E, Legendre F, et al. Interleukin-6 (IL-6) and/or soluble IL-6 receptor down-regulation of human type II collagen gene expression in articular chondrocytes requires a decrease of Sp1.Sp3 ratio and of the binding activity of both factors to the COL2A1 promoter. J Biol Chem. 2008;283(8):4850-65.
28. Harroch S, Revel M, Chebath J. Induction by interleukin-6 of interferon regulatory factor 1 (IRF-1) gene expression through the palindromic interferon response element pIRE and cell type-dependent control of IRF-1 binding to DNA. EMBO J. 1994;13(8):1942-9.
29. Huang SL, Chang TC, Chao CCK, Sun NK. TLR4/IL-6/IRF1 signaling regulates androgen receptor expression: A potential therapeutic target to overcome taxol resistance in ovarian cancer. Biochem Pharmacol. 2021;186:114456.
30. Cauvi DM, Cauvi G, Toomey CB, Jacquinet E, Pollard KM. From the Cover: Interplay Between IFN-γ and IL-6 Impacts the Inflammatory Response and Expression of Interferon-Regulated Genes in Environmental-Induced Autoimmunity. Toxicol Sci. 2017;158(1):227-39.
31. Zenke K, Muroi M, Tanamoto KI. IRF1 supports DNA binding of STAT1 by promoting its phosphorylation. Immunol Cell Biol. 2018;96(10):1095-103.
32. van Caam A, Vonk M, van den Hoogen F, van Lent P, van der Kraan P. Unraveling SSc Pathophysiology; The Myofibroblast. Front Immunol. 2018;9:2452.
33. Chrobak I, Lenna S, Stawski L, Trojanowska M. Interferon-γ promotes vascular remodeling in human microvascular endothelial cells by upregulating endothelin (ET)-1 and transforming growth factor (TGF) β2. J Cell Physiol. 2013;228(8):1774-83.
34. Lee M, Kim DW, Khalmuratova R, Shin SH, Kim YM, Han DH, et al. The IFN-γ-p38, ERK kinase axis exacerbates neutrophilic chronic rhinosinusitis by inducing the epithelial-to-mesenchymal transition. Mucosal Immunol. 2019;12(3):601-11.
35. Gu L, Zhu YJ, Guo ZJ, Xu XX, Xu WB. Effect of IFN-gamma and dexamethasone on TGF-beta1-induced human fetal lung fibroblast-myofibroblast differentiation. Acta Pharmacol Sin. 2004;25(11):1479-88.
36. Tanaka K, Sano K, Yuba K, Katsumura K, Nakano T, Tanaka K, et al. Inhibition of induction of myofibroblasts by interferon gamma in a human fibroblast cell line. Int Immunopharmacol. 2003;3(9):1273-80.
37. Zhang Y, Zhang J, Feng D, Zhou H, Gui Z, Zheng M, et al. IRF1/ZNF350/GPX4-mediated ferroptosis of renal tubular epithelial cells promote chronic renal allograft interstitial fibrosis. Free Radic Biol Med. 2022;193:579-94.
38. Uyama N, Tsutsui H, Wu S, Yasuda K, Hatano E, Qin X-Y, et al. Anti-interleukin-6 receptor antibody treatment ameliorates postoperative adhesion formation. Sci Rep. 2019;9(1):17558.
39. Goldsmith AM, Hershenson MB, Wolbert MP, Bentley JK. Regulation of airway smooth muscle alpha-actin expression by glucocorticoids. Am J Physiol Lung Cell Mol Physiol. 2007;292(1):L99-L106.
40. Grassegger A, Schuler G, Hessenberger G, Walder-Hantich B, Jabkowski J, MacHeiner W, et al. Interferon-gamma in the treatment of systemic sclerosis: a randomized controlled multicentre trial. Br J Dermatol. 1998;139(4):639-48.
41. Black CM, Silman AJ, Herrick AI, Denton CP, Wilson H, Newman J, et al. Interferon-alpha does not improve outcome at one year in patients with diffuse cutaneous scleroderma: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 1999;42(2):299-305.
42. Hu Y, Fu J, Liu X, Xue X. ERK1/2 Signaling Pathway Activated by EGF Promotes Proliferation, Transdifferentiation, and Migration of Cultured Primary Newborn Rat Lung Fibroblasts. Biomed Res Int. 2020;2020:7176169.
43. Zhou J, Sun X, Zhang J, Yang Y, Chen D, Cao J. IL-34 regulates IL-6 and IL-8 production in human lung fibroblasts via MAPK, PI3K-Akt, JAK and NF-κB signaling pathways. Int Immunopharmacol. 2018;61:119-25.
2. Sadeghi Shaker M, Rokni M, Mahmoudi M, Farhadi E. Ras family signaling pathway in immunopathogenesis of inflammatory rheumatic diseases. Front Immunol. 2023;14. English.
3. Ototake Y, Yamaguchi Y, Asami M, Komitsu N, Akita A, Watanabe T, et al. Downregulated IRF8 in monocytes and macrophages of patients with systemic sclerosis may aggravate the fibrotic phenotype. J Invest Dermatol. 2021;141(8):1954-63.
4. Skaug B, Assassi S. Type I interferon dysregulation in Systemic Sclerosis. Cytokine. 2020;132:154635.
5. Wu M, Assassi S. The role of type 1 interferon in systemic sclerosis. Front Immunol. 20136;4:266.
6. Gonçalves RSG, Pereira MC, Dantas AT, Almeida AR, Rego M, Lima EA, et al. CCL3, IL-7, IL-13 and IFNγ transcripts are increased in skin's biopsy of systemic sclerosis. Exp Dermatol. 2019;28(10):1172-5.
7. Wang WM, Li F, Jin HZ. Role of interferon regulatory factor-mediated signaling in psoriasis. Int J Med Sci. 2021;18(16):3794-9.
8. Wu M, Skaug B, Bi X, Mills T, Salazar G, Zhou X, et al. Interferon regulatory factor 7 (IRF7) represents a link between inflammation and fibrosis in the pathogenesis of systemic sclerosis. Ann Rheum Dis. 2019;78(11):1583-91.
9. Wu M, Salazar G, Ying J, Charles J, Zhou X, Mayes MD, et al., editors. Interferon Regulatory Factor (IRF) 7 in Type I IFN Signaling Represents As a Key Upstream Regulator in Early Diffuse SSc Patients and Plays Critical Role in Pathogenesis of Fibrosis. Arthritis Rheumatol; 2017: WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ USA.
10. Li Y, Liu Y, Huang Y, Yang K, Xiao T, Xiong J, et al. IRF‐1 promotes renal fibrosis by downregulation of Klotho. FASEB J. 2020;34(3):4415-29.
11. González-Serna D, Ochoa E, López-Isac E, Julià A, Degenhardt F, Ortego-Centeno N, et al. A cross-disease meta-GWAS identifies four new susceptibility loci shared between systemic sclerosis and Crohn's disease. Sci Rep. 2020;10(1):1862.
12. Zeng Z, Wang Y, Xiao Y, Zheng J, Liu R, He X, et al. Overexpression of OASL upregulates TET1 to induce aberrant activation of CD4(+) T cells in systemic sclerosis via IRF1 signaling. Arthritis Res Ther. 2022;24(1):50.
13. Li Y, Zhao J, Yin Y, Li K, Zhang C, Zheng Y. The Role of IL-6 in Fibrotic Diseases: Molecular and Cellular Mechanisms. Int J Biol Sci. 2022;18(14):5405-14.
14. Khan K, Xu S, Nihtyanova S, Derrett-Smith E, Abraham D, Denton CP, et al. Clinical and pathological significance of interleukin 6 overexpression in systemic sclerosis. Ann Rheum Dis. 2012;71(7):1235-42.
15. Van Den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheumatol. 2013;65(11):2737-47.
16. Medsger Jr T. Systemic sclerosis (scleroderma) localized scleroderma, eosinophilic fasciitis, and calcinosis. Arthritis and allied conditions. 1993:1118-65.
17. Hungness ES, Luo GJ, Pritts TA, Sun X, Robb BW, Hershko D, et al. Transcription factors C/EBP-beta and -delta regulate IL-6 production in IL-1beta-stimulated human enterocytes. J Cell Physiol. 2002;192(1):64-70.
18. Dogra D, Dogra N, Gupta G, Mushtaq S. Dexamethasone-cyclophosphamide pulse therapy in systemic sclerosis: A retrospective study from a tertiary care hospital. Indian J Dermatol Venereol Leprol. 2017;83:494.
19. Han S, Bui NT, Ho MT, Kim YM, Cho M, Shin DB. Dexamethasone Inhibits TGF-β1-Induced Cell Migration by Regulating the ERK and AKT Pathways in Human Colon Cancer Cells Via CYR61. Cancer Res Treat. 2016;48(3):1141-53.
20. Iudici M, Vettori S, Russo B, Giacco V, Capocotta D, Valentini G. Outcome of a glucocorticoid discontinuation regimen in patients with inactive systemic sclerosis. Clin Rheumatol. 2016;35(8):1985-91.
21. de Almeida AR, Dantas AT, Pereira MC, Cordeiro MF, Gonçalves RSG, de Melo Rêgo MJB, et al. Dexamethasone inhibits cytokine production in PBMC from systemic sclerosis patients. Inflammopharmacology. 2019;27(4):723-30.
22. Wang W, Xia X, Mao L, Wang S. The CCAAT/Enhancer-Binding Protein Family: Its Roles in MDSC Expansion and Function. Front Immunol. 2019;10.
23. Nunez BS, Geng CD, Pedersen KB, Millro-Macklin CD, Vedeckis WV. Interaction between the interferon signaling pathway and the human glucocorticoid receptor gene 1A promoter. Endocrinology. 2005;146(3):1449-57.
24. Yuan W, Yufit T, Li L, Mori Y, Chen SJ, Varga J. Negative modulation of α1 (I) procollagen gene expression in human skin fibroblasts: Transcriptional inhibition by interferon‐γ. J Cell Physiol. 1999;179(1):97-108.
25. Flammer JR, Dobrovolna J, Kennedy MA, Chinenov Y, Glass CK, Ivashkiv LB, et al. The type I interferon signaling pathway is a target for glucocorticoid inhibition. Mol Cell Biol. 2010;30(19):4564-74.
26. Barnes TC, Anderson ME, Moots RJ. The many faces of interleukin-6: the role of IL-6 in inflammation, vasculopathy, and fibrosis in systemic sclerosis. Int J Rheumatol. 2011;2011:721608.
27. Porée B, Kypriotou M, Chadjichristos C, Beauchef G, Renard E, Legendre F, et al. Interleukin-6 (IL-6) and/or soluble IL-6 receptor down-regulation of human type II collagen gene expression in articular chondrocytes requires a decrease of Sp1.Sp3 ratio and of the binding activity of both factors to the COL2A1 promoter. J Biol Chem. 2008;283(8):4850-65.
28. Harroch S, Revel M, Chebath J. Induction by interleukin-6 of interferon regulatory factor 1 (IRF-1) gene expression through the palindromic interferon response element pIRE and cell type-dependent control of IRF-1 binding to DNA. EMBO J. 1994;13(8):1942-9.
29. Huang SL, Chang TC, Chao CCK, Sun NK. TLR4/IL-6/IRF1 signaling regulates androgen receptor expression: A potential therapeutic target to overcome taxol resistance in ovarian cancer. Biochem Pharmacol. 2021;186:114456.
30. Cauvi DM, Cauvi G, Toomey CB, Jacquinet E, Pollard KM. From the Cover: Interplay Between IFN-γ and IL-6 Impacts the Inflammatory Response and Expression of Interferon-Regulated Genes in Environmental-Induced Autoimmunity. Toxicol Sci. 2017;158(1):227-39.
31. Zenke K, Muroi M, Tanamoto KI. IRF1 supports DNA binding of STAT1 by promoting its phosphorylation. Immunol Cell Biol. 2018;96(10):1095-103.
32. van Caam A, Vonk M, van den Hoogen F, van Lent P, van der Kraan P. Unraveling SSc Pathophysiology; The Myofibroblast. Front Immunol. 2018;9:2452.
33. Chrobak I, Lenna S, Stawski L, Trojanowska M. Interferon-γ promotes vascular remodeling in human microvascular endothelial cells by upregulating endothelin (ET)-1 and transforming growth factor (TGF) β2. J Cell Physiol. 2013;228(8):1774-83.
34. Lee M, Kim DW, Khalmuratova R, Shin SH, Kim YM, Han DH, et al. The IFN-γ-p38, ERK kinase axis exacerbates neutrophilic chronic rhinosinusitis by inducing the epithelial-to-mesenchymal transition. Mucosal Immunol. 2019;12(3):601-11.
35. Gu L, Zhu YJ, Guo ZJ, Xu XX, Xu WB. Effect of IFN-gamma and dexamethasone on TGF-beta1-induced human fetal lung fibroblast-myofibroblast differentiation. Acta Pharmacol Sin. 2004;25(11):1479-88.
36. Tanaka K, Sano K, Yuba K, Katsumura K, Nakano T, Tanaka K, et al. Inhibition of induction of myofibroblasts by interferon gamma in a human fibroblast cell line. Int Immunopharmacol. 2003;3(9):1273-80.
37. Zhang Y, Zhang J, Feng D, Zhou H, Gui Z, Zheng M, et al. IRF1/ZNF350/GPX4-mediated ferroptosis of renal tubular epithelial cells promote chronic renal allograft interstitial fibrosis. Free Radic Biol Med. 2022;193:579-94.
38. Uyama N, Tsutsui H, Wu S, Yasuda K, Hatano E, Qin X-Y, et al. Anti-interleukin-6 receptor antibody treatment ameliorates postoperative adhesion formation. Sci Rep. 2019;9(1):17558.
39. Goldsmith AM, Hershenson MB, Wolbert MP, Bentley JK. Regulation of airway smooth muscle alpha-actin expression by glucocorticoids. Am J Physiol Lung Cell Mol Physiol. 2007;292(1):L99-L106.
40. Grassegger A, Schuler G, Hessenberger G, Walder-Hantich B, Jabkowski J, MacHeiner W, et al. Interferon-gamma in the treatment of systemic sclerosis: a randomized controlled multicentre trial. Br J Dermatol. 1998;139(4):639-48.
41. Black CM, Silman AJ, Herrick AI, Denton CP, Wilson H, Newman J, et al. Interferon-alpha does not improve outcome at one year in patients with diffuse cutaneous scleroderma: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 1999;42(2):299-305.
42. Hu Y, Fu J, Liu X, Xue X. ERK1/2 Signaling Pathway Activated by EGF Promotes Proliferation, Transdifferentiation, and Migration of Cultured Primary Newborn Rat Lung Fibroblasts. Biomed Res Int. 2020;2020:7176169.
43. Zhou J, Sun X, Zhang J, Yang Y, Chen D, Cao J. IL-34 regulates IL-6 and IL-8 production in human lung fibroblasts via MAPK, PI3K-Akt, JAK and NF-κB signaling pathways. Int Immunopharmacol. 2018;61:119-25.
| Files | ||
| Issue | Vol 23 No 2 (2024) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v23i2.15325 | |
| Keywords | ||
| Dexamethasone Fibrosis Inflammation Interferon-γ IRF1 Systemic sclerosis | ||
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How to Cite
1.
Rokni M, Farhadi E, Kavosi H, Akhtari M, Madreseh E, Enayati S, Sadeghi Shaker M, Mostafaei S, Gharibdoost F, Mahmoudi M, Vodjgani M. Interferon-γ Induces Interleukin-6 Production and Alpha-smooth Muscle Actin Expression in Systemic Sclerosis Fibroblasts. Iran J Allergy Asthma Immunol. 2024;23(2):197-220.
