Dual roles of immunoregulatory cytokine TGF-β in the pathogenesis of autoimmunity-mediated organ damage

Vijay Saxena, Douglas W. Lienesch, Min Zhou, Ramireddy Bommireddy, Mohamad Azhar, Thomas C Doetschman, Ram Raj Singh

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

Ample evidence suggests a role of TGF-β in preventing autoimmunity. Multiorgan inflammatory disease, spontaneous activation of self-reactive T cells, and autoantibody production are hallmarks of autoimmune diseases, such as lupus. These features are reminiscent of the immunopathology manifest in TGF-β1-deficient mice. In this study, we show that lupus-prone (New Zealand Black and White)F1 mice have reduced expression of TGF-β1 in lymphoid tissues, and TGF-β1 or TGF-β1-producing T cells suppress autoantibody production. In contrast, the expression of TGF-β1 protein and mRNA and TGF-β signaling proteins (TGF-β receptor type II and phosphorylated SMAD3) increases in the target organs, i.e., kidneys, of these mice as they age and develop progressive organ damage. In fact, the levels of TGF-β1 in kidney tissue and urine correlate with the extent of chronic lesions that represent local tissue fibrosis. In vivo TGF-β blockade by treatment of these mice with an anti-TGF-β Ab selectively inhibits chronic fibrotic lesions without affecting autoantibody production and the inflammatory component of tissue injury. Thus, TGF-β plays a dual, seemingly paradoxical, role in the development of organ damage in multiorgan autoimmune diseases. According to our working model, reduced TGF-β in immune cells predisposes to immune dysregulation and autoantibody production, which causes tissue inflammation that triggers the production of anti-inflammatory cytokines such as TGF-β in target organs to counter inflammation. Enhanced TGF-β in target organs, in turn, can lead to dysregulated tissue repair, progressive fibrogenesis, and eventual end-organ damage.

Original languageEnglish (US)
Pages (from-to)1903-1912
Number of pages10
JournalJournal of Immunology
Volume180
Issue number3
StatePublished - Feb 1 2008

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Autoimmunity
Autoantibodies
Cytokines
Autoimmune Diseases
Inflammation
T-Lymphocytes
Kidney
Lymphoid Tissue
New Zealand
Proteins
Fibrosis
Anti-Inflammatory Agents
Urine
Messenger RNA
Wounds and Injuries

ASJC Scopus subject areas

  • Immunology

Cite this

Saxena, V., Lienesch, D. W., Zhou, M., Bommireddy, R., Azhar, M., Doetschman, T. C., & Singh, R. R. (2008). Dual roles of immunoregulatory cytokine TGF-β in the pathogenesis of autoimmunity-mediated organ damage. Journal of Immunology, 180(3), 1903-1912.

Dual roles of immunoregulatory cytokine TGF-β in the pathogenesis of autoimmunity-mediated organ damage. / Saxena, Vijay; Lienesch, Douglas W.; Zhou, Min; Bommireddy, Ramireddy; Azhar, Mohamad; Doetschman, Thomas C; Singh, Ram Raj.

In: Journal of Immunology, Vol. 180, No. 3, 01.02.2008, p. 1903-1912.

Research output: Contribution to journalArticle

Saxena, V, Lienesch, DW, Zhou, M, Bommireddy, R, Azhar, M, Doetschman, TC & Singh, RR 2008, 'Dual roles of immunoregulatory cytokine TGF-β in the pathogenesis of autoimmunity-mediated organ damage', Journal of Immunology, vol. 180, no. 3, pp. 1903-1912.
Saxena, Vijay ; Lienesch, Douglas W. ; Zhou, Min ; Bommireddy, Ramireddy ; Azhar, Mohamad ; Doetschman, Thomas C ; Singh, Ram Raj. / Dual roles of immunoregulatory cytokine TGF-β in the pathogenesis of autoimmunity-mediated organ damage. In: Journal of Immunology. 2008 ; Vol. 180, No. 3. pp. 1903-1912.
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