Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Fibrotic disease and the TH1/TH2 paradigm

Key Points

  • The tissue-repair process involves two distinct stages: a regenerative phase, in which injured cells are replaced by cells of the same type, leaving no lasting evidence of damage; and a phase known as fibroplasia or fibrotic scarring, in which connective tissue replaces normal parenchymal tissue.

  • Despite their obvious aetiological and clinical distinctions, most fibrotic diseases share a common paradigm characterized by a persistent inflammatory stimulus and lymphocyte–monocyte interactions that generate fibrogenic cytokines, which stimulate the deposition of connective tissue.

  • However, fibrosis is not always linked with robust inflammation, indicating that the mechanisms regulating fibrogenesis are distinct. Experiments using knockout mice have shown that fibrogenesis is associated with 'anti-inflammatory' T helper 2 (TH2) CD4+ T-cell responses, whereas pro-inflammatory TH1-cell responses are inhibitory.

  • Interleukin-4 (IL-4), IL-5 and IL-13, the signature TH2 cytokines, have distinct roles in the regulation of tissue remodelling and fibrosis. However, results from various experimental models indicate that IL-13 is the master regulator.

  • Transforming growth factor-β1 (TGF-β1) has been linked with the fibrosis that occurs in several diseases. Macrophages are an important source of TGF-β1, which directly activates collagen deposition by fibroblasts.

  • IL-13-secreting CD4+ TH2 cells regulate fibrogenesis directly by stimulating collagen synthesis by fibroblasts and indirectly by promoting TGF-β1 production by macrophages. IL-13 induces the production of, and activates, TGF-β1, by upregulating the expression of matrix metalloproteinases that cleave the latency-associated peptide.

  • Chemokines are strong leukocyte chemoattractants that cooperate with pro-fibrotic cytokines by recruiting macrophages and other effector cells to sites of tissue damage. CC-chemokine ligand 3 (CCL3; also known as macrophage inflammatory protein 1α) and several related CC-chemokines have been identified as essential pro-fibrotic mediators.

  • Macrophages and fibroblasts operate as key effector cells in the pathogenesis of fibrosis. The preferential activation of arginase 1 versus nitric-oxide synthase 2 in these cells might explain the potent pro-fibrotic activity of IL-13 and the antifibrotic activity of interferon-γ.

  • An attractive antifibrotic strategy would exploit the natural suppressive mechanisms of the host, which include regulatory T cells, IL-10 and the IL-13 decoy receptor.

  • Because of its ability to activate the wound-healing response, it might be more accurate to describe the TH2-cell response as an 'adaptive tissue-healing mechanism', instead of as a simple counter-regulatory system for the TH1-cell response.

Abstract

Tissue fibrosis (scarring) is a leading cause of morbidity and mortality. Current treatments for fibrotic disorders, such as idiopathic pulmonary fibrosis, hepatic fibrosis and systemic sclerosis, target the inflammatory cascade, but they have been widely unsuccessful, largely because the mechanisms that are involved in fibrogenesis are now known to be distinct from those involved in inflammation. Several experimental models have recently been developed to dissect the molecular mechanisms of wound healing and fibrosis. It is hoped that by better understanding the immunological mechanisms that initiate, sustain and suppress the fibrotic process, we will achieve the elusive goal of targeted and effective therapeutics for fibroproliferative diseases.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The pathogenesis of fibrotic disease.
Figure 2: Opposing roles for TH1 and TH2 cytokines in fibrosis.
Figure 3: IL-13 and TGF-β might function independently or cooperatively to promote collagen deposition by fibroblasts.
Figure 4: Regulatory T cells, IL-10 and IL-13Rα2 function as endogenous inhibitors of tissue fibrosis.

Similar content being viewed by others

References

  1. Cotran, R. S., Kumar, V. & Collins, T. in Pathologic Basis of Disease Vol. 6 (eds Cotran, R. S., Kumar, V. & Collins, T.) 89–112 (W. B. Saunders Company, Philadelphia, 1999).

    Google Scholar 

  2. Wynn, T. A. et al. An IL-12-based vaccination method for preventing fibrosis induced by schistosome infection. Nature 376, 594–596 (1995). An early example of the opposing activities of T H 1 and T H 2 responses in a progressive fibrotic disease.

    Article  CAS  PubMed  Google Scholar 

  3. Hoffmann, K. F., Cheever, A. W. & Wynn, T. A. IL-10 and the dangers of immune polarization: excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis. J. Immunol. 164, 6406–6416 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Gurujeyalakshmi, G. & Giri, S. N. Molecular mechanisms of antifibrotic effect of interferon-γ in bleomycin-mouse model of lung fibrosis: downregulation of TGF-β and procollagen I and III gene expression. Exp. Lung Res. 21, 791–808 (1995).

    Article  CAS  PubMed  Google Scholar 

  5. Keane, M. P., Belperio, J. A., Burdick, M. D. & Strieter, R. M. IL-12 attenuates bleomycin-induced pulmonary fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 281, L92–L97 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Oldroyd, S. D., Thomas, G. L., Gabbiani, G. & El Nahas, A. M. Interferon-γ inhibits experimental renal fibrosis. Kidney Int. 56, 2116–2127 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Poynard, T., Yuen, M. F., Ratziu, V. & Lai, C. L. Viral hepatitis C. Lancet 362, 2095–2100 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Hesse, M., Cheever, A. W., Jankovic, D. & Wynn, T. A. NOS-2 mediates the protective anti-inflammatory and antifibrotic effects of the TH1-inducing adjuvant, IL-12, in a TH2 model of granulomatous disease. Am. J. Pathol. 157, 945–955 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hoffmann, K. F. et al. Disease fingerprinting with cDNA microarrays reveals distinct gene expression profiles in lethal type 1 and type 2 cytokine-mediated inflammatory reactions. FASEB J. 15, 2545–2547 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Sandler, N. G., Mentink-Kane, M. M., Cheever, A. W. & Wynn, T. A. Global gene expression profiles during acute pathogen-induced pulmonary inflammation reveal divergent roles for TH1 and TH2 responses in tissue repair. J. Immunol. 171, 3655–3667 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Walker, L. S. & Abbas, A. K. The enemy within: keeping self-reactive T cells at bay in the periphery. Nature Rev. Immunol. 2, 11–19 (2002).

    Article  CAS  Google Scholar 

  12. Hesse, M. et al. Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of L-arginine metabolism. J. Immunol. 167, 6533–6544 (2001). The first report to show a functional link between T H 1/T H 2 responses and NOS2/ARG1 activity in an experimental model of fibrosis.

    Article  CAS  PubMed  Google Scholar 

  13. Decitre, M. et al. Lysyl oxidase-like protein localizes to sites of de novo fibrinogenesis in fibrosis and in the early stromal reaction of ductal breast carcinomas. Lab. Invest. 78, 143–151 (1998).

    CAS  PubMed  Google Scholar 

  14. Wang, S. & Hirschberg, R. BMP7 antagonizes TGF-β-dependent fibrogenesis in mesangial cells. Am. J. Physiol. Renal Physiol. 284, F1006–F1013 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Underwood, D. C. et al. SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung. Am. J. Physiol. Lung Cell. Mol. Physiol. 279, L895–L902 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Kim, H. et al. TIMP-1 deficiency does not attenuate interstitial fibrosis in obstructive nephropathy. J. Am. Soc. Nephrol. 12, 736–748 (2001).

    CAS  PubMed  Google Scholar 

  17. Vaillant, B., Chiaramonte, M. G., Cheever, A. W., Soloway, P. D. & Wynn, T. A. Regulation of hepatic fibrosis and extracellular matrix genes by the TH response: new insight into the role of tissue inhibitors of matrix metalloproteinases. J. Immunol. 167, 7017–7026 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Kaminski, N. et al. Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and fibrosis. Proc. Natl Acad. Sci. USA 97, 1778–1783 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kristensen, D. B. et al. Proteome analysis of rat hepatic stellate cells. Hepatology 32, 268–277 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Emura, M. et al. In vitro production of B cell growth factor and B cell differentiation factor by peripheral blood mononuclear cells and bronchoalveolar lavage T lymphocytes from patients with idiopathic pulmonary fibrosis. Clin. Exp. Immunol. 82, 133–139 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wallace, W. A., Ramage, E. A., Lamb, D. & Howie, S. E. A type 2 (TH2-like) pattern of immune response predominates in the pulmonary interstitium of patients with cryptogenic fibrosing alveolitis (CFA). Clin. Exp. Immunol. 101, 436–441 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Booth, M. et al. Periportal fibrosis in human Schistosoma mansoni infection is associated with low IL-10, low IFN-γ, high TNF-α, or low RANTES, depending on age and gender. J. Immunol. 172, 1295–1303 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Buttner, C. et al. Local production of interleukin-4 during radiation-induced pneumonitis and pulmonary fibrosis in rats: macrophages as a prominent source of interleukin-4. Am. J. Respir. Cell Mol. Biol. 17, 315–325 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Fertin, C. et al. Interleukin-4 stimulates collagen synthesis by normal and scleroderma fibroblasts in dermal equivalents. Cell. Mol. Biol. 37, 823–829 (1991).

    CAS  PubMed  Google Scholar 

  25. Letterio, J. J. & Roberts, A. B. Regulation of immune responses by TGF-β. Annu. Rev. Immunol. 16, 137–161 (1998). A comprehensive review of the biological activities of TGF-β in health and disease.

    Article  CAS  PubMed  Google Scholar 

  26. Sempowski, G. D., Beckmann, M. P., Derdak, S. & Phipps, R. P. 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. 152, 3606–3614 (1994).

    CAS  PubMed  Google Scholar 

  27. Doucet, C. et al. Interleukin (IL) 4 and IL-13 act on human lung fibroblasts. Implication in asthma. J. Clin. Invest. 101, 2129–2139 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tiggelman, A. M., Boers, W., Linthorst, C., Sala, M. & Chamuleau, R. A. Collagen synthesis by human liver (myo)fibroblasts in culture: evidence for a regulatory role of IL-1β, IL-4, TGF-β and IFN-γ. J. Hepatol. 23, 307–317 (1995).

    CAS  PubMed  Google Scholar 

  29. Cheever, A. W. et al. Anti-IL-4 treatment of Schistosoma mansoni-infected mice inhibits development of T cells and non-B, non-T cells expressing TH2 cytokines while decreasing egg-induced hepatic fibrosis. J. Immunol. 153, 753–759 (1994).

    CAS  PubMed  Google Scholar 

  30. Ong, C., Wong, C., Roberts, C. R., Teh, H. S. & Jirik, F. R. Anti-IL-4 treatment prevents dermal collagen deposition in the tight-skin mouse model of scleroderma. Eur. J. Immunol. 28, 2619–2629 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Le Moine, A. et al. Critical roles for IL-4, IL-5, and eosinophils in chronic skin allograft rejection. J. Clin. Invest. 103, 1659–1667 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zurawski, S. M., Vega, F. Jr, Huyghe, B. & Zurawski, G. Receptors for interleukin-13 and interleukin-4 are complex and share a novel component that functions in signal transduction. EMBO J. 12, 2663–2670 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. McKenzie, G. J. et al. Impaired development of TH2 cells in IL-13-deficient mice. Immunity 9, 423–432 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. Zhu, Z. et al. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J. Clin. Invest. 103, 779–788 (1999). The first report to show the potent pro-fibrotic activity of IL-13 when overexpressed in the lung.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Donaldson, D. D. et al. The murine IL-13 receptor α2: molecular cloning, characterization, and comparison with murine IL-13 receptor α1. J. Immunol. 161, 2317–2324 (1998).

    CAS  PubMed  Google Scholar 

  36. Chiaramonte, M. G., Donaldson, D. D., Cheever, A. W. & Wynn, T. A. An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response. J. Clin. Invest. 104, 777–785 (1999). The first experimental study to show that an IL-13 inhibitor can block the development of fibrosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Blease, K. et al. Therapeutic effect of IL-13 immunoneutralization during chronic experimental fungal asthma. J. Immunol. 166, 5219–5224 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Kumar, R. K. et al. Role of interleukin-13 in eosinophil accumulation and airway remodelling in a mouse model of chronic asthma. Clin. Exp. Allergy 32, 1104–1111 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Chiaramonte, M. G., Cheever, A. W., Malley, J. D., Donaldson, D. D. & Wynn, T. A. Studies of murine schistosomiasis reveal interleukin-13 blockade as a treatment for established and progressive liver fibrosis. Hepatology 34, 273–282 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Fallon, P. G., Richardson, E. J., McKenzie, G. J. & McKenzie, A. N. Schistosome infection of transgenic mice defines distinct and contrasting pathogenic roles for IL-4 and IL-13: IL-13 is a profibrotic agent. J. Immunol. 164, 2585–2591 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Belperio, J. A. et al. Interaction of IL-13 and C10 in the pathogenesis of bleomycin-induced pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 27, 419–427 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Rankin, J. A. et al. Phenotypic and physiologic characterization of transgenic mice expressing interleukin 4 in the lung: lymphocytic and eosinophilic inflammation without airway hyperreactivity. Proc. Natl Acad. Sci. USA 93, 7821–7825 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Murata, T., Husain, S. R., Mohri, H. & Puri, R. K. Two different IL-13 receptor chains are expressed in normal human skin fibroblasts, and IL-4 and IL-13 mediate signal transduction through a common pathway. Int. Immunol. 10, 1103–1110 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. Oriente, A. et al. Interleukin-13 modulates collagen homeostasis in human skin and keloid fibroblasts. J. Pharmacol. Exp. Ther. 292, 988–994 (2000).

    CAS  PubMed  Google Scholar 

  45. Saito, A., Okazaki, H., Sugawara, I., Yamamoto, K. & Takizawa, H. Potential action of IL-4 and IL-13 as fibrogenic factors on lung fibroblasts in vitro. Int. Arch. Allergy Immunol. 132, 168–176 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Blease, K. et al. Stat6-deficient mice develop airway hyperresponsiveness and peribronchial fibrosis during chronic fungal asthma. Am. J. Pathol. 160, 481–490 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Webb, D. C. et al. Integrated signals between IL-13, IL-4, and IL-5 regulate airways hyperreactivity. J. Immunol. 165, 108–113 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Walter, D. M. et al. Critical role for IL-13 in the development of allergen-induced airway hyperreactivity. J. Immunol. 167, 4668–4675 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Webb, D. C. et al. Antigen-specific production of interleukin (IL)-13 and IL-5 cooperate to mediate IL-4Rα-independent airway hyperreactivity. Eur. J. Immunol. 33, 3377–3385 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Gharaee-Kermani, M. & Phan, S. H. Lung interleukin-5 expression in murine bleomycin-induced pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 16, 438–447 (1997).

    Article  CAS  PubMed  Google Scholar 

  51. Sher, A., Coffman, R. L., Heiny, S., Scott, P. & Cheever, A. W. Interleukin 5 is required for the blood and tissue eosinophilia but not granuloma formation induced by infection with Schistosoma mansoni. Proc. Natl Acad. Sci. USA 87, 61–64 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hao, H., Cohen, D. A., Jennings, C. D., Bryson, J. S. & Kaplan, A. M. Bleomycin-induced pulmonary fibrosis is independent of eosinophils. J. Leukoc. Biol. 68, 515–521 (2000).

    CAS  PubMed  Google Scholar 

  53. Gharaee-Kermani, M. et al. The role of IL-5 in bleomycin-induced pulmonary fibrosis. J. Leukoc. Biol. 64, 657–666 (1998).

    Article  CAS  PubMed  Google Scholar 

  54. Blyth, D. I., Wharton, T. F., Pedrick, M. S., Savage, T. J. & Sanjar, S. Airway subepithelial fibrosis in a murine model of atopic asthma: suppression by dexamethasone or anti-interleukin-5 antibody. Am. J. Respir. Cell Mol. Biol. 23, 241–246 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Cho, J. Y. et al. Inhibition of airway remodeling in IL-5-deficient mice. J. Clin. Invest. 113, 551–560 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Huaux, F. et al. Eosinophils and T lymphocytes possess distinct roles in bleomycin-induced lung injury and fibrosis. J. Immunol. 171, 5470–5481 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Mattes, J. et al. Intrinsic defect in T cell production of interleukin (IL)-13 in the absence of both IL-5 and eotaxin precludes the development of eosinophilia and airways hyperreactivity in experimental asthma. J. Exp. Med. 195, 1433–1444 (2002). An important study identifying a link between IL-5, CCL11, eosinophils and IL-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sato, M., Muragaki, Y., Saika, S., Roberts, A. B. & Ooshima, A. Targeted disruption of TGF-β1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. J. Clin. Invest. 112, 1486–1494 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Border, W. A. et al. Natural inhibitor of transforming growth factor-β protects against scarring in experimental kidney disease. Nature 360, 361–364 (1992). This study showed the effect of blocking TGF-β in the treatment of fibrotic kidney disease.

    Article  CAS  PubMed  Google Scholar 

  60. Clouthier, D. E., Comerford, S. A. & Hammer, R. E. Hepatic fibrosis, glomerulosclerosis, and a lipodystrophy-like syndrome in PEPCK–TGF-β1 transgenic mice. J. Clin. Invest. 100, 2697–2713 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sime, P. J., Xing, Z., Graham, F. L., Csaky, K. G. & Gauldie, J. Adenovector-mediated gene transfer of active transforming growth factor-β1 induces prolonged severe fibrosis in rat lung. J. Clin. Invest. 100, 768–776 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gorelik, L. & Flavell, R. A. Transforming growth factor-β in T-cell biology. Nature Rev. Immunol. 2, 46–53 (2002).

    Article  CAS  Google Scholar 

  63. Munger, J. S. et al. The integrin-αvβ6 binds and activates latent TGF-β1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96, 319–328 (1999).

    Article  CAS  PubMed  Google Scholar 

  64. Roberts, A. B., Russo, A., Felici, A. & Flanders, K. C. Smad3: a key player in pathogenetic mechanisms dependent on TGF-β. Ann. NY Acad. Sci. 995, 1–10 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Flanders, K. C. et al. Mice lacking Smad3 are protected against cutaneous injury induced by ionizing radiation. Am. J. Pathol. 160, 1057–1068 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Khalil, N., Corne, S., Whitman, C. & Yacyshyn, H. Plasmin regulates the activation of cell-associated latent TGF-β1 secreted by rat alveolar macrophages after in vivo bleomycin injury. Am. J. Respir. Cell Mol. Biol. 15, 252–259 (1996).

    Article  CAS  PubMed  Google Scholar 

  67. Ma, L. J. et al. Transforming growth factor-β-dependent and -independent pathways of induction of tubulointerstitial fibrosis in β6−/− mice. Am. J. Pathol. 163, 1261–1273 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ashcroft, G. S. et al. Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nature Cell Biol. 1, 260–266 (1999). The first study to implicate SMAD3 in specific pathways of tissue repair, indicating that SMAD3 might inhibit, rather than induce, the tissue-healing pathway.

    Article  CAS  PubMed  Google Scholar 

  69. Kaviratne, M. et al. IL-13 activates a mechanism of liver fibrosis that is completely TGF-β independent. J. Immunol. (in the press).

  70. Lee, C. G. et al. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor β1. J. Exp. Med. 194, 809–821 (2001). An important study that showed that IL-13 induces and activates latent TGF-β1 by an MMP9- and plasmin/serine protease-dependent mechanism.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Lanone, S. et al. Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and -12 in IL-13-induced inflammation and remodeling. J. Clin. Invest. 110, 463–474 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Nakao, A. et al. Blockade of transforming growth factor-β/Smad signaling in T cells by overexpression of Smad7 enhances antigen-induced airway inflammation and airway reactivity. J. Exp. Med. 192, 151–158 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hansen, G. et al. CD4+ T helper cells engineered to produce latent TGF-β1 reverse allergen-induced airway hyperreactivity and inflammation. J. Clin. Invest. 105, 61–70 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kitani, A. et al. Transforming growth factor (TGF)- β1-producing regulatory T cells induce Smad-mediated interleukin 10 secretion that facilitates coordinated immunoregulatory activity and amelioration of TGF-β1-mediated fibrosis. J. Exp. Med. 198, 1179–1188 (2003). This study showed that TGF-β1-producing regulatory T cells stimulate IL-10 production, which suppresses bleomycin-induced fibrosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Kulkarni, A. B. et al. Transforming growth factor β1 null mutation in mice causes excessive inflammatory response and early death. Proc. Natl Acad. Sci. USA 90, 770–774 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Smith, R. E. et al. Production and function of murine macrophage inflammatory protein-1α in bleomycin-induced lung injury. J. Immunol. 153, 4704–4712 (1994). The first report to establish an important role for CC-chemokines in fibrotic lung disease.

    CAS  PubMed  Google Scholar 

  77. Smith, R. E. et al. A role for CC chemokines in fibrotic lung disease. J. Leukoc. Biol. 57, 782–787 (1995).

    Article  CAS  PubMed  Google Scholar 

  78. Lloyd, C. M. et al. RANTES and monocyte chemoattractant protein-1 (MCP-1) play an important role in the inflammatory phase of crescentic nephritis, but only MCP-1 is involved in crescent formation and interstitial fibrosis. J. Exp. Med. 185, 1371–1380 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Belperio, J. A. et al. Critical role for the chemokine MCP-1/CCR2 in the pathogenesis of bronchiolitis obliterans syndrome. J. Clin. Invest. 108, 547–556 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Tokuda, A. et al. Pivotal role of CCR1-positive leukocytes in bleomycin-induced lung fibrosis in mice. J. Immunol. 164, 2745–2751 (2000).

    Article  CAS  PubMed  Google Scholar 

  81. Blease, K. et al. Airway remodeling is absent in CCR1−/− mice during chronic fungal allergic airway disease. J. Immunol. 165, 1564–1572 (2000).

    Article  CAS  PubMed  Google Scholar 

  82. Anders, H. J. et al. A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation. J. Clin. Invest. 109, 251–259 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Moore, B. B. et al. Protection from pulmonary fibrosis in the absence of CCR2 signaling. J. Immunol. 167, 4368–4377 (2001).

    Article  CAS  PubMed  Google Scholar 

  84. Zhu, Z. et al. IL-13-induced chemokine responses in the lung: role of CCR2 in the pathogenesis of IL-13-induced inflammation and remodeling. J. Immunol. 168, 2953–2962 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. Gao, J. L. et al. Impaired host defense, hematopoiesis, granulomatous inflammation and type 1/type 2 cytokine balance in mice lacking CC chemokine receptor 1. J. Exp. Med. 185, 1959–1968 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Ma, B. et al. The C10/CCL6 chemokine and CCR1 play critical roles in the pathogenesis of IL-13-induced inflammation and remodeling. J. Immunol. 172, 1872–1881 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Gordon, S. Alternative activation of macrophages. Nature Rev. Immunol. 3, 23–35 (2003).

    Article  CAS  Google Scholar 

  88. Munder, M., Eichmann, K. & Modolell, M. Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: competitive regulation by CD4+ T cells correlates with TH1/TH2 phenotype. J. Immunol. 160, 5347–5354 (1998).

    CAS  PubMed  Google Scholar 

  89. Munder, M. et al. TH1/TH2-regulated expression of arginase isoforms in murine macrophages and dendritic cells. J. Immunol. 163, 3771–3777 (1999).

    CAS  PubMed  Google Scholar 

  90. Witte, M. B., Barbul, A., Schick, M. A., Vogt, N. & Becker, H. D. Upregulation of arginase expression in wound-derived fibroblasts. J. Surg. Res. 105, 35–42 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Zimmermann, N. et al. Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis. J. Clin. Invest. 111, 1863–1874 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Hogaboam, C. M. et al. Collagen deposition in a non-fibrotic lung granuloma model after nitric oxide inhibition. Am. J. Pathol. 153, 1861–1872 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Numaguchi, K. et al. Chronic inhibition of nitric oxide synthesis causes coronary microvascular remodeling in rats. Hypertension 26, 957–962 (1995).

    Article  CAS  PubMed  Google Scholar 

  94. Moore, K. W., de Waal Malefyt, R., Coffman, R. L. & O'Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001).

    Article  CAS  PubMed  Google Scholar 

  95. Thompson, K. et al. Interleukin-10 expression and function in experimental murine liver inflammation and fibrosis. Hepatology 28, 1597–1606 (1998).

    Article  CAS  PubMed  Google Scholar 

  96. Louis, H. et al. Interleukin-10 controls neutrophilic infiltration, hepatocyte proliferation, and liver fibrosis induced by carbon tetrachloride in mice. Hepatology 28, 1607–1615 (1998).

    Article  CAS  PubMed  Google Scholar 

  97. Arai, T. et al. Introduction of the interleukin-10 gene into mice inhibited bleomycin-induced lung injury in vivo. Am. J. Physiol. Lung Cell. Mol. Physiol. 278, L914–L922 (2000).

    Article  CAS  PubMed  Google Scholar 

  98. Demols, A. et al. Endogenous interleukin-10 modulates fibrosis and regeneration in experimental chronic pancreatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 282, G1105–G1112 (2002).

    Article  CAS  PubMed  Google Scholar 

  99. Wangoo, A., Laban, C., Cook, H. T., Glenville, B. & Shaw, R. J. Interleukin-10- and corticosteroid-induced reduction in type I procollagen in a human ex vivo scar culture. Int. J. Exp. Pathol. 78, 33–41 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Wang, S. C., Ohata, M., Schrum, L., Rippe, R. A. & Tsukamoto, H. Expression of interleukin-10 by in vitro and in vivo activated hepatic stellate cells. J. Biol. Chem. 273, 302–308 (1998).

    Article  CAS  PubMed  Google Scholar 

  101. Nelson, D. R. et al. Long-term interleukin 10 therapy in chronic hepatitis C patients has a proviral and anti-inflammatory effect. Hepatology 38, 859–868 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. Wynn, T. A. et al. IL-10 regulates liver pathology in acute murine Schistosomiasis mansoni but is not required for immune down-modulation of chronic disease. J. Immunol. 160, 4473–4480 (1998).

    CAS  PubMed  Google Scholar 

  103. Hesse, M. et al. The pathogenesis of schistosomiasis is controlled by cooperating IL-10-producing innate effector and regulatory T cells. J. Immunol. 172, 3157–3166 (2004).

    Article  CAS  PubMed  Google Scholar 

  104. Lee, C. G. et al. Transgenic overexpression of interleukin (IL)-10 in the lung causes mucus metaplasia, tissue inflammation, and airway remodeling via IL-13-dependent and -independent pathways. J. Biol. Chem. 277, 35466–35474 (2002).

    Article  CAS  PubMed  Google Scholar 

  105. Taube, C. et al. The role of IL-13 in established allergic airway disease. J. Immunol. 169, 6482–6489 (2002).

    Article  CAS  PubMed  Google Scholar 

  106. Mattes, J. et al. IL-13 induces airways hyperreactivity independently of the IL-4R α-chain in the allergic lung. J. Immunol. 167, 1683–1692 (2001).

    Article  CAS  PubMed  Google Scholar 

  107. Feng, N. et al. The interleukin-4/interleukin-13 receptor of human synovial fibroblasts: overexpression of the nonsignaling interleukin-13 receptor α2. Lab. Invest. 78, 591–602 (1998).

    CAS  PubMed  Google Scholar 

  108. Wood, N. et al. Enhanced interleukin (IL)-13 responses in mice lacking IL-13 receptor α2. J. Exp. Med. 197, 703–709 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Chiaramonte, M. G. et al. Regulation and function of the interleukin 13 receptor α2 during a T helper cell type 2-dominant immune response. J. Exp. Med. 197, 687–701 (2003). This study provides evidence that IL-13Rα2 functions as a decoy receptor for IL-13. The development of liver fibrosis was accelerated in S. mansoni -infected IL-13Rα2-deficient mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Mentink-Kane, M. M. et al. IL-13 receptor α2 down-modulates granulomatous inflammation and prolongs host survival in schistosomiasis. Proc. Natl Acad. Sci. USA 101, 586–590 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. Zheng, T. et al. Cytokine regulation of IL-13Rα2 and IL-13Rα1 in vivo and in vitro. J. Allergy Clin. Immunol. 111, 720–728 (2003).

    Article  CAS  PubMed  Google Scholar 

  112. Jakubzick, C. et al. Impact of interleukin-13 responsiveness on the synthetic and proliferative properties of TH1- and TH2-type pulmonary granuloma fibroblasts. Am. J. Pathol. 162, 1475–1486 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Daines, M. O. & Hershey, G. K. A novel mechanism by which interferon-γ can regulate interleukin (IL)-13 responses. Evidence for intracellular stores of IL-13 receptor α-2 and their rapid mobilization by interferon-γ. J. Biol. Chem. 277, 10387–10393 (2002).

    Article  CAS  PubMed  Google Scholar 

  114. Wynn, T. A. et al. P-selectin suppresses hepatic inflammation and fibrosis in mice by regulating interferon-γ and the IL-13 decoy receptor. Hepatology 39, 676–687 (2004).

    Article  CAS  PubMed  Google Scholar 

  115. Clark, J. G., Dedon, T. F., Wayner, E. A. & Carter, W. G. Effects of interferon-γ on expression of cell surface receptors for collagen and deposition of newly synthesized collagen by cultured human lung fibroblasts. J. Clin. Invest. 83, 1505–1511 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Hansen, G., Berry, G., DeKruyff, R. H. & Umetsu, D. T. Allergen-specific TH1 cells fail to counterbalance TH2 cell-induced airway hyperreactivity but cause severe airway inflammation. J. Clin. Invest. 103, 175–183 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Randolph, D. A., Stephens, R., Carruthers, C. J. & Chaplin, D. D. Cooperation between TH1 and TH2 cells in a murine model of eosinophilic airway inflammation. J. Clin. Invest. 104, 1021–1029 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ford, J. G. et al. IL-13 and IFN-γ: interactions in lung inflammation. J. Immunol. 167, 1769–1777 (2001).

    Article  CAS  PubMed  Google Scholar 

  119. Castro, M., Chaplin, D. D., Walter, M. J. & Holtzman, M. J. Could asthma be worsened by stimulating the T-helper type 1 immune response? Am. J. Respir. Cell Mol. Biol. 22, 143–146 (2000).

    Article  CAS  PubMed  Google Scholar 

  120. Wills-Karp, M. et al. Interleukin-13: central mediator of allergic asthma. Science 282, 2258–2261 (1998).

    Article  CAS  PubMed  Google Scholar 

  121. Grunig, G. et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282, 2261–2263 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Marth, T., Strober, W., Seder, R. A. & Kelsall, B. L. Regulation of transforming growth factor-β production by interleukin-12. Eur. J. Immunol. 27, 1213–1220 (1997).

    Article  CAS  PubMed  Google Scholar 

  123. Nelson, D. R., Lauwers, G. Y., Lau, J. Y. & Davis, G. L. Interleukin 10 treatment reduces fibrosis in patients with chronic hepatitis C: a pilot trial of interferon nonresponders. Gastroenterology 118, 655–660 (2000).

    Article  CAS  PubMed  Google Scholar 

  124. Kaufman, J., Sime, P. J. & Phipps, R. P. Expression of CD154 (CD40 ligand) by human lung fibroblasts: differential regulation by IFN-γ and IL-13, and implications for fibrosis. J. Immunol. 172, 1862–1871 (2004).

    Article  CAS  PubMed  Google Scholar 

  125. Adawi, A. et al. Blockade of CD40–CD40 ligand interactions protects against radiation-induced pulmonary inflammation and fibrosis. Clin. Immunol. Immunopathol. 89, 222–230 (1998).

    Article  CAS  PubMed  Google Scholar 

  126. Katsuma, S. et al. Molecular monitoring of bleomycin-induced pulmonary fibrosis by cDNA microarray-based gene expression profiling. Biochem. Biophys. Res. Commun. 288, 747–751 (2001).

    Article  CAS  PubMed  Google Scholar 

  127. Kaminski, N. Microarray analysis of idiopathic pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 29, S32–S36 (2003).

    Article  CAS  PubMed  Google Scholar 

  128. Anders, R. A. et al. cDNA microarray analysis of macroregenerative and dysplastic nodules in end-stage hepatitis C virus-induced cirrhosis. Am. J. Pathol. 162, 991–1000 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Abbas, A. K., Murphy, K. M. & Sher, A. Functional diversity of helper T lymphocytes. Nature 383, 787–793 (1996).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I sincerely thank the many colleagues who have collaborated with our group over the past several years. I greatly appreciate the generous support of D. Donaldson, J. Sypek, M. Grusby, F. Lewis, A. Cheever, D. Dunne and A. Sher.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

Thomas A. Wynn is employed by the United States Department of Health and Human Services, which holds a patent position on the treatment of fibrosis by antagonizing interleukin-13 and the interleukin-13 receptor chains. He might benefit from its commercialization.

Related links

Related links

DATABASES

Entrez Gene

ARG1

CCL2

CCL3

CD4

IFN-γ

IL-4

IL-4Rα

IL-5

IL-10

IL-12

IL-13

IL-13Rα1

IL-13Rα2

MMP2

MMP9

NOS2

OAT

ODC

procollagen-I

procollagen-III

SMAD3

STAT6

TGF-β

TIMP1

Infectious Disease Information

schistosomiasis

FURTHER INFORMATION

Thomas Wynn's laboratory

Glossary

BLEOMYCIN

An antineoplastic antibiotic. It is active against bacteria and fungi, but its cytotoxicity has prevented its use as an anti-infective agent. Treatment with bleomycin is associated with significant pulmonary side effects — including fibrosis — that limit its use. Bleomycin was first noted to cause pulmonary fibrosis in the initial clinical trials in which it was tested. Since that time, it has been used extensively in experimental models to dissect the mechanisms of fibrosis.

CHRONIC GRANULOMATOUS RESPONSE

Granulomas are localized inflammatory reactions that contain T cells and are a form of delayed-type hypersensitivity. They have common features involving persistent antigenic stimulation that is not easily cleared by phagocytic cells. The cellular conglomerate is shielded from the healthy tissue by extracellular matrix. Granuloma formation and the fibrotic scarring that follows can cause progressive organ damage.

T HELPER 2 (TH2) CD4+ T-CELL RESPONSE

CD4+ T cells are classified according to the cytokines that they secrete. TH2 cells secrete large amounts of interleukin-4 (IL-4), IL-5 and IL-13, which promote antibody production by B cells and collagen synthesis by fibroblasts, whereas TH1 cells secrete large amounts of interferon-γ and associated pro-inflammatory cytokines. TH1-type and TH2-type cytokines can cross-regulate each other's responses. An imbalance of TH1/TH2 responses is thought to contribute to the pathogenesis of various infections, allergic responses and autoimmune diseases.

CpG-CONTAINING OLIGODEOXYNUCLEOTIDES

DNA oligodeoxynucleotide sequences that include a cytosine–guanosine sequence and certain flanking nucleotides. They have been found to induce innate immune responses through interaction with Toll-like receptor 9.

BRONCHOALVEOLAR LAVAGE

A diagnostic procedure conducted by placing a fibre-optic scope into the lung of a patient and injecting sterile saline into the lung to flush out free material. The sterile material removed contains secretions, cells and proteins from the lower respiratory tract.

CRYPTOGENIC FIBROSING ALVEOLITIS

Together with various other chronic lung disorders, cryptogenic fibrosing alveolitis is known as interstitial lung disease (ILD). ILD affects the lung in three ways: first, the tissue is damaged in some known or unknown way; second, the walls of the air sacs become inflamed; and third, scarring (or fibrosis) begins in the interstitium (tissue between the air sacs), and the lung becomes stiff.

SCLERODERMA

A chronic autoimmune disease that causes a hardening of the skin. The skin thickens because of increased deposits of collagen. There are two types of scleroderma. Localized scleroderma affects the skin in limited areas and the musculoskeletal system. Systemic sclerosis causes more widespread skin changes and can be associated with internal organ damage to the lungs, heart and kidneys.

CD4+CD25+ REGULATORY T CELLS

(TReg cells). A specialized subset of CD4+ T cells that can suppress other T-cell responses. These cells are characterized by expression of the interleukin-2 (IL-2) receptor β-chain (also known as CD25). In some cases, suppression has been associated with the secretion of IL-10, transforming growth factor-β or both.

sIL-13Rα2–Fc

A soluble protein that consists of the extracellular domain of the interleukin-13 receptor-α2 (IL-13Rα2) fused to a Gly-Ser-Gly spacer and the sequence encoding the hinge–heavy-chain constant region 2 (CH2)–CH3 regions of human IgG1. The resulting protein is a specific inhibitor of IL-13. The inhibitor prevents IL-13 from binding its signalling receptors and has been used successfully to block progressive fibrotic disease.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wynn, T. Fibrotic disease and the TH1/TH2 paradigm. Nat Rev Immunol 4, 583–594 (2004). https://doi.org/10.1038/nri1412

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1412

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing