Epithelial transglutaminase 2 is needed for T cell interleukin-17 production and subsequent pulmonary inflammation and fibrosis in bleomycin-treated mice
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Pulmonary fibrosis is a potentially life-threatening disease that may be caused by overt or asymptomatic inflammatory responses. However, the precise mechanisms by which tissue injury is translated into inflammation and consequent fibrosis remain to be established. Here, we show that in a lung injury model, bleomycin induced the secretion of IL-6 by epithelial cells in a transglutaminase 2 (TG2)–dependent manner. This response represents a key step in the differentiation of IL-17–producing T cells and subsequent inflammatory amplification in the lung. The essential role of epithelial cells, but not inflammatory cells, TG2 was confirmed in bone marrow chimeras; chimeras made in TG2-deficient recipients showed reduced inflammation and fibrosis, compared with those in wild-type mice, regardless of the bone marrow cell phenotype. Epithelial TG2 thus appears to be a critical inducer of inflammation after noninfectious pulmonary injury. We further demonstrated that fibroblast-derived TG2, acting downstream of transforming growth factor-β, is also important in the effector phase of fibrogenesis. Therefore, TG2 represents an interesting potential target for therapeutic intervention.
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Alarmin cytokines TSLP, IL-25, and IL-33 initiate type 2-dependent fibrosis by triggering production of IL-4 and IL-13 in innate lymphoid cells, T cells, eosinophils, and other type 2-associated leukocytes.
“the alarmin cytokines thymic stromal lymphopoietin, IL-25, and IL-33 function as key initiators of type 2-dependent fibrosis by triggering the production of IL-4 and IL-13 in innate lymphoid cells, T cells, eosinophils, and other type 2-associated leukocytes129–132”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [130]
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Self-citationOh, K., Moon, H., Lee, D., & Yoo, Y.-B. (2015) · Laboratory Animal Research · doi:10.5625/lar.2015.31.4.188 · Cited by 28 · see citing works
Self-citationTang, J., Huang, H., Ji, X., Zhu, X., Li, Y., She, M., Yan, S., Fung, M. C., & Li, Z. (2014) · Mediators of Inflammation · doi:10.1155/2014/753483 · Cited by 28 · see citing works
Transglutaminase 2 as a Marker for Inflammation and Therapeutic Target in Sepsis
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Self-citationJeong, E. M., Lee, K. B., Kim, G. E., Kim, C. M., Lee, J.-H., Kim, H.-J., Shin, J., Kwon, M.-A., Park, H. H., & Kim, I. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21030791 · Cited by 25 · see citing works
Self-citationMasui, Y., Asano, Y., Takahashi, T., Shibata, S., Akamata, K., Aozasa, N., Noda, S., Taniguchi, T., Ichimura, Y., Toyama, T., et al. (2012) · Modern Rheumatology · doi:10.1007/s10165-012-0660-7 · Cited by 25 · see citing works
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Cho, S., Jeong, E. M., Lee, J.-H., Kim, H.-J., Lim, J., Kim, C.-W., Shin, D., Jeon, J., Choi, K., & Kim, I. G. (2012) · Molecules and Cells · doi:10.1007/s10059-012-2201-9 · Cited by 22 · see citing works
Self-citationMasui, Y., Asano, Y., Takahashi, T., Shibata, S., Akamata, K., Aozasa, N., Noda, S., Taniguchi, T., Ichimura, Y., Toyama, T., et al. (2013) · Modern Rheumatology · doi:10.3109/s10165-012-0660-7 · Cited by 21 · see citing works
Implications of enigmatic transglutaminase 2 (TG2) in cardiac diseases and therapeutic developments
Al-U'datt, D. G. F., Tranchant, C. C., Al‐Dwairi, A., Alqudah, M., Al-Shboul, O. A., Hiram, R., Allen, B. G., Jaradat, S. A., Alqbelat, J., & Abu-zaiton, A. S. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115104 · Cited by 19 · see citing works
Gupta, G., Singh, Y. P., Tiwari, J., Raizaday, A., Alharbi, K. S., Al-Abbasi, F. A., Kazmi, I. A., Satija, S., Tambuwala, M. M., Devkota, H. P., et al. (2020) · Dermatologic Therapy · doi:10.1111/dth.14209 · Cited by 19 · see citing works
Jeong, E. M., Son, Y. H., Choi, Y., Kim, J. H., Lee, J.-H., Cho, S., & Kim, I. G. (2016) · Experimental & Molecular Medicine · doi:10.1038/emm.2016.95 · Cited by 17 · see citing works
Self-citationDivergent results induced by different types of septic shock in transglutaminase 2 knockout mice
Yoo, H. J., Ahn, E.-R., Kim, S.-J., Lee, S.-H., Oh, S. H., & Kim, S. (2012) · Amino Acids · doi:10.1007/s00726-012-1412-x · Cited by 17 · see citing works
Extracellular Targets to Reduce Excessive Scarring in Response to Tissue Injury
Fertala, J., Wang, M. L., Rivlin, M. R., Beredjiklian, P. K., Abboud, J. A., Arnold, W. V., & Fertala, A. (2023) · Biomolecules · doi:10.3390/biom13050758 · Cited by 16 · see citing works
Ablation of Glutaredoxin-1 Modulates House Dust Mite–Induced Allergic Airways Disease in Mice
Hoffman, S. M., Qian, X., Nolin, J. D., Chapman, D. G., Chia, S. B., Lahue, K. G., Schneider, R., Ather, J. L., Randall, M. J., McMillan, D. H., et al. (2016) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2015-0401oc · Cited by 16 · see citing works
Cystamine induces AIF-mediated apoptosis through glutathione depletion
Cho, S., Lee, J.-H., Ju, M.-K., Jeong, E. M., Kim, H.-J., Lim, J., Lee, S., Cho, N., Park, H. H., Choi, K., et al. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2014.12.028 · Cited by 15 · see citing works
Self-citationSpatially Resolved Identification of Transglutaminase Substrates by Proteomics in Pulmonary Fibrosis
Takeuchi, T., Tatsukawa, H., Shinoda, Y., Kuwata, K., Nishiga, M., Takahashi, H., Hase, N., & Hitomi, K. (2021) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2021-0012oc · Cited by 15 · see citing works
Wee, Y., Go, H., Choi, M. Y., Jung, H. R., Cho, Y. M., Kim, Y. H., Han, D. J., & Shin, S. H. (2019) · BMB Reports · doi:10.5483/bmbrep.2019.52.9.193 · Cited by 15 · see citing works
Self-citationMCTR1 Intervention Reverses Experimental Lung Fibrosis in Mice
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Kim, H.-J., Lee, J.-H., Lee, K. B., Shin, J., Kwon, M.-A., Lee, S., Jeong, E. M., Cho, S., & Kim, I. G. (2021) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-00549-9 · Cited by 13 · see citing works
Self-citationTransglutaminase 3 Reduces the Severity of Psoriasis in Imiquimod-Treated Mouse Skin
Piro, M. C., Ventura, A., Smirnov, A., Saggini, A., Lena, A. M., Mauriello, A., Bianchi, L., Melino, G., & Candi, E. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21051566 · Cited by 13 · see citing works
Self-citationTang, J., Zhu, X., Zhao, J., Fung, M. C., Li, Y., Gao, Z., Yan, S., Li, X., Ji, X., Fang, S., et al. (2015) · Mediators of Inflammation · doi:10.1155/2015/659378 · Cited by 12 · see citing works
Lee, H. S., Park, D.-E., Bae, B., Oh, K., Jung, J., Lee, D., Kim, I. G., Cho, S., & Kang, H. (2021) · Immunity Inflammation and Disease · doi:10.1002/iid3.442 · Cited by 12 · see citing works
Self-citationTransglutaminase 2 in cartilage homoeostasis: novel links with inflammatory osteoarthritis
Adamczyk, M. (2016) · Amino Acids · doi:10.1007/s00726-016-2305-1 · Cited by 11 · see citing works
Kim, M., Yu, H. Y., Ju, H., Shin, J. H., Kim, A., Lee, J. H., Ryu, C., Yun, H., Lee, S., Lim, J., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-52811-4 · Cited by 11 · see citing works
Self-citationKim, J. Y., Wee, Y., Choi, M. Y., Jung, H. R., Choi, J. Y., Kwon, H. W., Jung, J. H., Cho, Y. M., Go, H., Han, M., et al. (2019) · Annals of Surgical Treatment and Research · doi:10.4174/astr.2019.97.1.27 · Cited by 11 · see citing works
Self-citationPiro, M. C., Pecorari, R., Smirnov, A., Cappello, A., Foffi, E., Lena, A. M., Shi, Y., Melino, G., & Candi, E. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-07159-7 · Cited by 10 · see citing works
Self-citationAmelio, I., Knight, R. A., Lisitsa, A., Melino, G., & Antonov, A. V. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.42 · Cited by 10 · see citing works
Self-citationA Precision Strategy to Cure Renal Cell Carcinoma by Targeting Transglutaminase 2
Kim, S., & Keillor, J. W. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21072493 · Cited by 9 · see citing works
Lan, K., April, V., Jamali, F., Sabri, S., & Abdulkarim, B. (2025) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2025.104894 · Cited by 8 · see citing works
Chen, S., Liu, C., Hsieh, P., Liao, Y., Lin, Y.-M. J., Yu, C., & Yu, C.-H. (2019) · Journal of the Formosan Medical Association · doi:10.1016/j.jfma.2019.09.015 · Cited by 8 · see citing works
Hong, A.-Y., Lee, S., Lee, K. B., Shin, J., Jeong, E. M., & Kim, I. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052709 · Cited by 7 · see citing works
Self-citationFraser-Pitt, D. J., Mercer, D. K., Francis, M.-L. R., Toledo-Aparicio, D., Smith, D. W., & O′Neil, D. A. (2023) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2023.08.021 · Cited by 7 · see citing works
Rayavara, K., Kurosky, A., & Hosakote, Y. M. (2021) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00013.2021 · Cited by 7 · see citing works
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Enhanced transglutaminase 2 expression in response to stress-related catecholamines in macrophages
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Kim, Y. C., Kim, J., Kim, S. H., Bae, B., Kim, R. L., Jeong, E. M., Cho, S., & Kang, H. (2021) · Experimental Lung Research · doi:10.1080/01902148.2021.1998733 · Cited by 6 · see citing works
Self-citationIntimal Hyperplasia in Loop-Injured Carotid Arteries Is Attenuated in Transglutaminase 2-Null Mice
Min, S.-K., Min, S., Jeong, E. M., Cho, S., Ha, J., Kim, S. J., & Kim, I. G. (2014) · Journal of Korean Medical Science · doi:10.3346/jkms.2014.29.3.363 · Cited by 6 · see citing works
Self-citationCancer Stem Cells in the Immune Microenvironment
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Self-citationYuan, X., Jia, M., Zhou, L., Hou, G., Zhang, B., Ouyang, X., & Huang, Y. (2025) · Kidney Medicine · doi:10.1016/j.xkme.2025.101122 · Cited by 5 · see citing works
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Transglutaminase2: An Enduring Enzyme in Diabetes and Age-Related Metabolic Diseases
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Molecular signatures of alveolar type II cell differentiation in acute respiratory distress syndrome
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Effects of Transglutaminase 2 Inhibition on Ventilator-Induced Lung Injury
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Role of IL-17 cytokines in tubal fibrosis and infertility due to salpingitis
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- Authors
- Oh, K., Park, H.-B., Byoun, O.-J., Shin, D.-M., Jeong, E. M., Kim, Y. W., Kim, Y. S., Melino, G., Kim, I.-G., & Lee, D.-S.
- Affiliations
- Seoul National University (KR)
- University of Leicester (GB)
- Corresponding author
- Kim, In-Gyu
- Lee, Dong-Sup
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2011-07-11
- Volume
- 208
- Issue
- 8
- Pages
- 1707-1719
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC3149214
- OpenAlex
- W2139169478
- Cited by
- 118
- References
- 47
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 3 · 2023: 6 · 2022: 5 · 2021: 13 · 2020: 9 · 2019: 7 · 2018: 6 · 2017: 4 · 2016: 10 · 2015: 9 · 2014: 11 · 2013: 14 · 2012: 8
- FWCI
- 9.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Leicester Research Archive (University of Leicester) (submittedVersion, cc-by-nc-sa)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Health Sciences › Medicine › Pathology and Forensic Medicine › Systemic Sclerosis and Related Diseases
- Keywords
- IL-17, T cell differentiation, pulmonary fibrosis, bleomycin-induced lung injury, IL-6 secretion, lung epithelial cells, lung inflammation, TGF-beta, bone marrow chimeras, fibrogenesis
- MeSH terms
- Protein Glutamine gamma Glutamyltransferase 2, Amines, Animals, Biotin, Bleomycin, Collagen, Enzyme-Linked Immunosorbent Assay, Epithelial Cells, Flow Cytometry, Fluorescent Antibody Technique, Histological Techniques, Male, Mice, Inbred C57BL, Pneumonia, Transglutaminases, Pulmonary Fibrosis, RNA, T-Lymphocytes, Blotting, Western, Interleukin-6, Polymerase Chain Reaction, DNA Primers, Mice, Knockout, Bronchoalveolar Lavage, GTP-Binding Proteins, Interleukin-17, Mice
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