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Activation of Th2 cells leads to Increased cellular proliferation and differentiation
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Substance interaction with the lung resident cell membrane components leading to lung fibrosis||adjacent||High||Low||Cataia Ives (send email)||Under development: Not open for comment. Do not cite||EAGMST Under Review|
Life Stage Applicability
Key Event Relationship Description
The wound healing process involves an inflammatory phase, during which the damage tissue/wound is provisionally filled with ECM. This phase is characterised by secretion of cytokines/chemokines, growth factors and recruitment of inflammatory cells, fibroblasts and endothelial cells. The activated Th1/Th2 response and increased pool of specific cytokines and growth factors such as IL-1b, IL-6, IL-13, and TGFβ, induce fibroblast proliferation. Th2 cells can directly stimulate fibroblasts to synthesise collagen with IL-1 and IL-13. Th2 cytokines IL-13 and IL-4, known to mediate the fibrosis process induce phenotypic transition of human fibroblasts (Hashimoto S, 2001). IL-13 is shown to inhibit MMP-mediated matrix degradation resulting in excessive collagen deposition by downregulating the synthesis and expression of matrix degrading MMPs. IL-13 is also suggested to induce TGFβ1 in macrophages and its absence results in reduced TGFβ1 expression and decrease in collagen deposition (Fichtner-Feigl et al., 2005). These cytokines are suggested to initiate polarisation of macrophages to the alternative M2 phenotype. Th2 cells that synthesise IL-4 and IL-13 induce synthesis of Arg-1 in M2 macrophages. The Arg-1 pathway stimulates synthesis of proline for collagen synthesis required for fibrosis (Barron and Wynn, 2011).
Evidence Collection Strategy
Evidence Supporting this KER
The biological plausibility for this KER is high. There is a widely understood functional relationship between Th2 response related mediators, and their ability to induce proliferation and differentiation of fibroblasts (Shao et al., 2008; Wynn, 2012; Wynn, 2004).
Uncertainties and Inconsistencies
Due to multifarious functions of several cytokines involved in the process of inflammation and repair, the timing of when a pathway is intervened in an experiment is important in the assessment of the KER studies. For example, exposure to pro-fibrotic bleomycin stimulates IL-4 production during the acute inflammatory phase, which is suggested to limit the recruitment of T lymphocytes and production of damaging cytokines such as TNFα, IFNγ, and nitric oxide, playing a tissue protective role. However, production of IL- 4 during the chronic phase of tissue repair and healing, favors fibrosis manifestation. Treatment of IL4 -/- mice with low doses of bleomycin induced fewer fibrotic lesions compared to IL-4 +/+ mice. However, treatment of high doses of bleomycin induced more lethality in IL-4 -/- mice compared to the wild type mice (Huaux et al., 2003). Moreover, the KEs represented in AOP 173 can function in parallel in a positive feedback loop, perpetuating and magnifying the response at each stage. The resulting microenvironment may contain the same molecules in different proportions exhibiting different functions. Thus, the complexity of the process and the functional heterogeneity of the molecular players involved, makes it nearly impossible to establish KERs using a targeted deletion of one single gene or a pathway in a study, which is how most of the studies are designed.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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- Barron, L. and Wynn, T. (2011). Fibrosis is regulated by Th2 and Th17 responses and by dynamic interactions between fibroblasts and macrophages. American Journal of Physiology-Gastrointestinal and Liver Physiology, 300(5), pp.G723-G728
- Cao H et al. Hydrogen sulfide protects against bleomycin-induced pulmonary fibrosis in rats by inhibiting NF-B expression and regulating Th1/Th2 balance. Toxicology Letters, 2014, 224, 387-394
- Dong, J., Porter, D., Batteli, L., Wolfarth, M., Richardson, D. and Ma, Q. (2014). Pathologic and molecular profiling of rapid-onset fibrosis and inflammation induced by multi-walled carbon nanotubes. Archives of Toxicology, 89(4), pp.621-633
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- Fichtner-Feigl, S., Strober, W., Kawakami, K., Puri, R. and Kitani, A. (2005). IL-13 signaling through the IL-13α2 receptor is involved in induction of TGF-β1 production and fibrosis. Nature Medicine, 12(1), pp.99-106.
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- Halappanavar, S., Nikota, J., Wu, D., Williams, A., Yauk, C. and Stampfli, M. (2013). IL-1 Receptor Regulates microRNA-135b Expression in a Negative Feedback Mechanism during Cigarette Smoke–Induced Inflammation. The Journal of Immunology, 190(7), pp.3679-3686
- Hashimoto, S., Gon, Y., Takeshita, I., Maruoka, S. and Horie, T. (2001). IL-4 and IL-13 induce myofibroblastic phenotype of human lung fibroblasts through c-Jun NH2-terminal kinase–dependent pathway. Journal of Allergy and Clinical Immunology, 107(6), pp.1001-1008
- Huaux, F., Liu, T., McGarry, B., Ullenbruch, M. and Phan, S. (2003). Dual Roles of IL-4 in Lung Injury and Fibrosis. The Journal of Immunology, 170(4), pp.2083-2092
- Kurosaka, H., Kurosaka, D., Kato, K., Mashima, Y., & Tanaka, Y. (1998). Transforming growth factor-beta 1 promotes contraction of collagen gel by bovine corneal fibroblasts through differentiation of myofibroblasts.
- Lee, C. G., Homer, R. J., Zhu, Z., Lanone, S., Wang, X., Koteliansky, V., Shipley, J. M., Gotwals, P., Noble, P., Chen, Q., Senior, R. M., & Elias, J. A. (2001). Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1). The Journal of experimental medicine, 194(6), 809–821.
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- Lo Re, S et al. Platelet-derived growth factor-producing CD4+Foxp3+ regulatory T lymphocytes promote lung fibrosis. Am J Respir Crit Care Med, 2011. 184, 1270-1281.
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- Nikota, J., Banville, A., Goodwin, L. R., Wu, D., Williams, A., Yauk, C. L., Wallin, H., Vogel, U., & Halappanavar, S. (2017). Stat-6 signaling pathway and not Interleukin-1 mediates multi-walled carbon nanotube-induced lung fibrosis in mice: insights from an adverse outcome pathway framework. Particle and fibre toxicology, 14(1), 37. https://doi.org/10.1186/s12989-017-0218-0
- Postlethwaite, A., Holness, M., Katai, H. and Raghow, R. (1992). Human fibroblasts synthesize elevated levels of extracellular matrix proteins in response to interleukin 4. Journal of Clinical Investigation, 90(4), pp.1479-1485
- Sempowski, G. D., Beckmann, M. P., Derdak, S., & Phipps, R. P. (1994). Subsets of murine lung fibroblasts express membrane-bound and soluble IL-4 receptors. Role of IL-4 in enhancing fibroblast proliferation and collagen synthesis. Journal of immunology (Baltimore, Md. : 1950), 152(7), 3606–3614.
- Shao, D. D., Suresh, R., Vakil, V., Gomer, R. H., & Pilling, D. (2008). Pivotal Advance: Th-1 cytokines inhibit, and Th-2 cytokines promote fibrocyte differentiation. Journal of leukocyte biology, 83(6), 1323–1333. https://doi.org/10.1189/jlb.1107782
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- Wallace, W. and Howie, S. (1999). Immunoreactive interleukin 4 and interferon-? expression by type II alveolar epithelial cells in interstitial lung disease. The Journal of Pathology, 187(4), pp.475-480.
- Wynes M et al. IL-4 induced macrophage-derived IGF-1 protects myofibroblasts from apoptosis following growth factor withdrawal. Journal of Leukocyte Biology, 2004, 76, 1019-1027
- Wynn, T. Fibrotic disease and the TH1/TH2 paradigm. Nat Rev Immunol 4, 583–594 (2004). https://doi.org/10.1038/nri1412
- Wynn, T. A., & Ramalingam, T. R. (2012). Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nature medicine, 18(7), 1028–1040. https://doi.org/10.1038/nm.2807
- Yin H et al. IL-33 accelerates cutaneous wound healing involved in upregulation of alternatively activated macrophages. Molecular immunology, 2013, 56, 347-353