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Thymosin β 4 sulfoxide is an anti-inflammatory agent generated by monocytes in the presence of glucocorticoids

Nature Medicine volume 5, pages 1424–1427 (1999)Cite this article

Abstract

The possibility that glucocorticoids upregulate the expression of anti-inflammatory mediators is an exciting prospect for therapy in inflammatory diseases, because these molecules could give the therapeutic benefits of steroids without toxic side effects1,2. Supernatants from monocytes3 and macrophages4 cultured in the presence of glucocorticoids increase the dispersion of neutrophils from a cell pellet in the capillary tube migration assay. This supernatant factor, unlike other neutrophil agonists, promotes dispersive locomotion of neutrophils at uniform concentration, lowers their adhesion to endothelial cells, inhibits their chemotactic response to fMLP and induces distinctive morphological changes5,6. Here we show that thymosin β4 sulfoxide is generated by monocytes in the presence of glucocorticoids and acts as a signal to inhibit an inflammatory response. In vitro, thymosin β4 sulfoxide inhibited neutrophil chemotaxis, and in vivo, the oxidized peptide, but not the native form, was a potent inhibitor of carrageenin-induced edema in the mouse paw. Thymosin β4 is unique, because oxidation attenuates its intracellular G-actin sequestering activity7, but greatly enhances its extracellular signaling properties. This description of methionine oxidation conferring extracellular function on a cytosolic protein8 may have far-reaching implications for future strategies of anti-inflammatory therapy.

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Figure 1: Purification and identification of the active factor present in the monocyte supernatant.
Figure 2: Comparison of Tβ4 and Tβ4so by in vitro assays.
Figure 3: Tβ4so, but not Tβ4, suppressed footpad swelling after carrageenin-induced inflammation in BALB/c mice.

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Acknowledgements

We thank G. Kemp (Cell and Molecular Biology Division, University of St. Andrews, UK) or guidance, and N. O'Reilly and D. Gadhia of the peptide synthesis group (Imperial Cancer Research Fund), for the preparation of synthetic peptides. This work was supported by the Fraser Foundation, The Sylvia Aitken Trust, The Wellcome Trust and the Imperial Cancer Research Fund.

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Authors and Affiliations

  1. Division of Infection and Immunity, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK

    J.D. Young & A.J. Lawrence

  2. New England Regional Primate Research Center, Harvard Medical School, Southborough, 01772, Massachusetts, USA

    A.G. MacLean

  3. Department of Immunology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK

    B.P. Leung

  4. Department of Medicine, Centre for Rheumatic Diseases, Glasgow Royal Infirmary, Alexandra Parade, Glasgow, G31 2ES, UK

    I.B. McInnes

  5. Protein Sequencing Laboratory, Imperial Cancer Research Fund, Lincoln's Inn Fields, London, WC2A 3PX, UK

    B. Canas & D.J.C. Pappin

  6. Department of Respiratory Medicine, Glasgow Royal Infirmary, Alexandra Parade, Glasgow, G31 2ES, UK

    R.D. Stevenson

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Correspondence to A.J. Lawrence.

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Young, J., Lawrence, A., MacLean, A. et al. Thymosin β 4 sulfoxide is an anti-inflammatory agent generated by monocytes in the presence of glucocorticoids. Nat Med 5, 1424–1427 (1999). https://doi.org/10.1038/71002

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