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Relationship: 1706


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Activation of Th2 cells leads to Increased cellular proliferation and differentiation

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Substance interaction with the pulmonary resident cell membrane components leading to pulmonary fibrosis adjacent High Low Sabina Halappanavar (send email) Under development: Not open for comment. Do not cite WPHA/WNT Endorsed

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

The wound healing process involves an inflammatory phase, during which the damage tissue/wound is provisionally filled with extracellular matrix (ECM). This phase is characterised by secretion of cytokines/chemokines, growth factors and recruitment of inflammatory cells, fibroblasts and endothelial cells. The activated T helper (Th)1/Th2 response and increased pool of specific cytokines and growth factors such as Interleukin (IL)-1β, IL-6, IL-13, and Transforming growth factor beta (TGF-β), induce fibroblast proliferation. Th type 2 (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 et al., 2001). IL-13 is shown to inhibit Matrix metalloproteinases (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 TGF-β1 in macrophages and its absence results in reduced TGF-β1 expression and decrease in collagen deposition (Fichtner-Feigl et al., 2006). These cytokines are suggested to initiate polarisation of macrophages to the alternative phenotype (M2). Th2 cells that synthesise IL-4 and IL-13 induce synthesis of Arginase (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

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

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, 2004; Wynn, 2012).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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 Tumor necrosis factor alpha (TNF-α), IFN-γ, 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

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help


List of the literature that was cited for this KER description. More help
  1. Ando M, Miyazaki E, Fukami T, Kumamoto T, Tsuda T. Interleukin-4-producing cells in idiopathic pulmonary fibrosis: an immunohistochemical study. Respirology. 1999 Dec;4(4):383-91. doi: 10.1046/j.1440-1843.1999.00209.x.

  2. Barron L, Wynn TA. Fibrosis is regulated by Th2 and Th17 responses and by dynamic interactions between fibroblasts and macrophages. Am J Physiol Gastrointest Liver Physiol. 2011 May;300(5):G723-8. doi: 10.1152/ajpgi.00414.2010. 

  3. Cao H, Zhou X, Zhang J, Huang X, Zhai Y, Zhang X, Chu L. Hydrogen sulfide protects against bleomycin-induced pulmonary fibrosis in rats by inhibiting NF-κB expression and regulating Th1/Th2 balance. Toxicol Lett. 2014 Jan 30;224(3):387-94. doi: 10.1016/j.toxlet.2013.11.008. 

  4. Dong J, Ma Q. In vivo activation of a T helper 2-driven innate immune response in lung fibrosis induced by multi-walled carbon nanotubes. Arch Toxicol. 2016 Sep;90(9):2231-2248. doi: 10.1007/s00204-016-1711-1.

  5. Fichtner-Feigl S, Strober W, Kawakami K, Puri RK, Kitani A. IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis. Nat Med. 2006 Jan;12(1):99-106. doi: 10.1038/nm1332.

  6. Gibbons MA, MacKinnon AC, Ramachandran P, Dhaliwal K, Duffin R, Phythian-Adams AT, van Rooijen N, Haslett C, Howie SE, Simpson AJ, Hirani N, Gauldie J, Iredale JP, Sethi T, Forbes SJ. Ly6Chi monocytes direct alternatively activated profibrotic macrophage regulation of lung fibrosis. Am J Respir Crit Care Med. 2011 Sep 1;184(5):569-81. doi: 10.1164/rccm.201010-1719OC.

  7. Hashimoto S, Gon Y, Takeshita I, Maruoka S, Horie T. IL-4 and IL-13 induce myofibroblastic phenotype of human lung fibroblasts through c-Jun NH2-terminal kinase-dependent pathway. J Allergy Clin Immunol. 2001 Jun;107(6):1001-8. doi: 10.1067/mai.2001.114702. 

  8. Huaux F, Liu T, McGarry B, Ullenbruch M, Phan SH. Dual roles of IL-4 in lung injury and fibrosis. J Immunol. 2003 Feb 15;170(4):2083-92. doi: 10.4049/jimmunol.170.4.2083.

  9. Kurosaka H, Kurosaka D, Kato K, Mashima Y, Tanaka Y. Transforming growth factor-beta 1 promotes contraction of collagen gel by bovine corneal fibroblasts through differentiation of myofibroblasts. Invest Ophthalmol Vis Sci. 1998 Apr;39(5):699-704. 

  10. Lee CG, Homer RJ, Zhu Z, Lanone S, Wang X, Koteliansky V, Shipley JM, Gotwals P, Noble P, Chen Q, Senior RM, Elias JA. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1). J Exp Med. 2001 Sep 17;194(6):809-21. doi: 10.1084/jem.194.6.809.

  11. Li D, Guabiraba R, Besnard AG, Komai-Koma M, Jabir MS, Zhang L, Graham GJ, Kurowska-Stolarska M, Liew FY, McSharry C, Xu D. IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice. J Allergy Clin Immunol. 2014 Dec;134(6):1422-1432.e11. doi: 10.1016/j.jaci.2014.05.011. 

  12. Liu T, Baek HA, Yu H, Lee HJ, Park BH, Ullenbruch M, Liu J, Nakashima T, Choi YY, Wu GD, Chung MJ, Phan SH. FIZZ2/RELM-β induction and role in pulmonary fibrosis. J Immunol. 2011 Jul 1;187(1):450-61. doi: 10.4049/jimmunol.1000964. 

  13. Lo Re S, Lecocq M, Uwambayinema F, Yakoub Y, Delos M, Demoulin JB, Lucas S, Sparwasser T, Renauld JC, Lison D, Huaux F. Platelet-derived growth factor-producing CD4+ Foxp3+ regulatory T lymphocytes promote lung fibrosis. Am J Respir Crit Care Med. 2011 Dec 1;184(11):1270-81. doi: 10.1164/rccm.201103-0516OC. 

  14. Meziani L, Mondini M, Petit B, Boissonnas A, Thomas de Montpreville V, Mercier O, Vozenin MC, Deutsch E. CSF1R inhibition prevents radiation pulmonary fibrosis by depletion of interstitial macrophages. Eur Respir J. 2018 Mar 1;51(3):1702120. doi: 10.1183/13993003.02120-2017.

  15. Nikota J, Banville A, Goodwin LR, Wu D, Williams A, Yauk CL, Wallin H, Vogel U, Halappanavar S. 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. Part Fibre Toxicol. 2017 Sep 13;14(1):37. doi: 10.1186/s12989-017-0218-0. 

  16. Postlethwaite AE, Holness MA, Katai H, Raghow R. Human fibroblasts synthesize elevated levels of extracellular matrix proteins in response to interleukin 4. J Clin Invest. 1992 Oct;90(4):1479-85. doi: 10.1172/JCI116015.

  17. Redington AE, Madden J, Frew AJ, Djukanovic R, Roche WR, Holgate ST, Howarth PH. Transforming growth factor-beta 1 in asthma. Measurement in bronchoalveolar lavage fluid. Am J Respir Crit Care Med. 1997 Aug;156(2 Pt 1):642-7. doi: 10.1164/ajrccm.156.2.9605065.

  18. Sempowski GD, Beckmann MP, Derdak S, Phipps RP. Subsets of murine lung fibroblasts express membrane-bound and soluble IL-4 receptors. Role of IL-4 in enhancing fibroblast proliferation and collagen synthesis. J Immunol. 1994 Apr 1;152(7):3606-14. 

  19. Shao DD, Suresh R, Vakil V, Gomer RH, Pilling D. Pivotal Advance: Th-1 cytokines inhibit, and Th-2 cytokines promote fibrocyte differentiation. J Leukoc Biol. 2008 Jun;83(6):1323-33. doi: 10.1189/jlb.1107782. 

  20. Wallace WA, Howie SE. Immunoreactive interleukin 4 and interferon-gamma expression by type II alveolar epithelial cells in interstitial lung disease. J Pathol. 1999 Mar;187(4):475-80. doi: 10.1002/(SICI)1096-9896(199903)187:4<475::AID-PATH268>3.0.CO;2-N. 

  21. Wynes MW, Frankel SK, Riches DW. IL-4-induced macrophage-derived IGF-I protects myofibroblasts from apoptosis following growth factor withdrawal. J Leukoc Biol. 2004 Nov;76(5):1019-27. doi: 10.1189/jlb.0504288.

  22. Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol. 2004 Aug;4(8):583-94. doi: 10.1038/nri1412.

  23. Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012 Jul 6;18(7):1028-40. doi: 10.1038/nm.2807. 

  24. Yin H, Li X, Hu S, Liu T, Yuan B, Gu H, Ni Q, Zhang X, Zheng F. IL-33 accelerates cutaneous wound healing involved in upregulation of alternatively activated macrophages. Mol Immunol. 2013 Dec;56(4):347-53. doi: 10.1016/j.molimm.2013.05.225.