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.

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.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

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.

References

  1. Cato, C.B. & Wade, M.E. Molecular mechanisms of anti-inflammatory action of glucocorticoids. Bioessays 18, 371–378 (1996).

    Article  CAS  Google Scholar 

  2. Abbinante-Nissen, J.M., Simpson, L.G. & Leikauf, G.D. Corticosteroids increase secretory leukocyte protease inhibitor transcript levels in airway epithelial cells. Am. J. Physiol. 268, 601–606 (1995).

    Google Scholar 

  3. Stevenson, R.D. Mechanism of anti-inflammatory action of glucocorticosteroids. Lancet i, 225–226 (1977).

    Article  Google Scholar 

  4. Stevenson, R.D. Studies on the production and action of polymorph migration stimulator Clin. Exp Immunol. 24, 527–533 (1976).

    CAS  Google Scholar 

  5. Chettibi, S., Lawrence, A.J., Young, J.D. & Stevenson, R.D., Dispersive locomotion of human neutrophils in response to a steroid-induced factor from monocytes. J. Cell Sci. 107, 3173–3181 (1994).

    CAS  Google Scholar 

  6. Young, J.D., MacLean, A.G., Lawrence, A.J., Stevenson, R.D. & Chettibi, S. Relationship of human neutrophil morphology and actin distribution to dispersive locomotion caused by a steroid-induced factor. Exp. Biol. Online 2, 7 (1997).

    Article  Google Scholar 

  7. Heintz, D. et al. The sulfoxide of thymosin beta-4 almost lacks the polymerization- inhibiting capacity for actin. Eur. J. Biochem. 223, 345–350 (1994).

    Article  CAS  Google Scholar 

  8. Jeffrey, C.J. Moonlighting proteins. Trends Biochem. Sci. 24 8–11 (1999).

    Article  Google Scholar 

  9. Sherman, N.E. et al. in Proc. 43rd ASMS Conf. Mass Spectrom. Allied Top. 626–627 (Atlanta, Georgia, 21–26 May, 1995).

    Google Scholar 

  10. Thurman, G.R., Seals, C., Low, T.L.K. & Goldstein, A.L. Restorative effects of thymosin polypeptides on purified protein derivative-dependent migration inhibition factor production by the peripheral blood lymphocytes of adult thymectomized guinea pigs. J. Biol. Resp. Mod. 3, 160–173 (1984).

    CAS  Google Scholar 

  11. Cassimeris, L., Safer, D., Nachmias, V.T. & Zigmond, S.H. Thymosin β4 sequesters the majority of G-actin in resting human polymorphonuclear leukocytes. J. Cell Biol. 119, 1261–1270 (1992).

    Article  CAS  Google Scholar 

  12. Malinda, K,M., Goldstein, A.L. & Kleinman, H.M. Thymosin β4 stimulates directional migration of human umbilical vein endothelial cells. FASEB J. 11, 472–481 (1997).

    Article  Google Scholar 

  13. Ianaro, A., O'Donnell, C.A., Di Rosa, M., & Liew, F.Y. A nitric oxide synthase inhibitor reduces inflammation, downregulates inflammatory cytokines and enhances interleukin-10 production in carrageenan induced oedema in mice. Immunology 82, 370–375 (1994).

    CAS  Google Scholar 

  14. Nachmias, V.T. Small actin-binding proteins: the β-thymosin family. Curr. Opin. Cell Biol. 5, 56–62 (1993).

    Article  CAS  Google Scholar 

  15. Feinberg, J., Hertz, F., Benjamin, V. & Roustan, C. The N-terminal sequence (5–20) of thymosin β4 binds to monomeric actin in an α-helical conformation. Biochem. Biophys. Res. Comm. 222, 127–132 (1996).

    Article  CAS  Google Scholar 

  16. Watson, A.A., Fairlie, D.P. & Craik, D.J. Solution structure of methionine-oxidized amyloid beta-peptide (1-40). Does oxidation affect conformational switching? Biochemistry 37, 12700–12706 (1998).

    Article  CAS  Google Scholar 

  17. Swaim M.W. & Pizzo S.V. Methionine sulphoxide and the oxidative regulation of plasma proteinase inhibitors. J. Leuk. Biol. 43, 365–379 (1988).

    Article  CAS  Google Scholar 

  18. Vogt, W. Oxidation of methionyl residues in proteins: tools, targets, and reversal. Free Radic. Biol. Med. 18, 93–105 (1995).

    Article  CAS  Google Scholar 

  19. Levine, R. L., Mosoni, L., Berlett, B.S. & Stadtman, E.R. Methionine residues as endogenous antioxidants in proteins. Proc. Nat. Acad. Sci. USA 93, 15036–15040 (1996).

    Article  CAS  Google Scholar 

  20. Beck-Speier I., Leuschel L., Luippold G. & Maier K. L. Proteins released from human neutrophils contain very high levels of oxidized methionine. FEBS Lett. 227, 1–4, (1988).

    Article  CAS  Google Scholar 

  21. Fliss H., Weissbach H. & Brot N. Oxidation of methionine residues in proteins of activated human neutrophils. Proc. Natl. Acad. Sci. USA 80, 7160–7164 (1983).

    Article  CAS  Google Scholar 

  22. Ciorba, M.A., Heinemann, S.H., Weissbach, H., Brot, N. & Hoshi, T. Modulation of potassium channel function by methionine oxidation and reduction. Proc. Natl. Acad. Sci. USA 94, 9932–9937 (1997).

    Article  CAS  Google Scholar 

  23. Moskovitz, J. et al. Overexpression of peptide-methionine sulfoxide reductase in Saccharomyces cerevisiae and human T cells provides them with high resistance to oxidative stress. Proc. Natl. Acad. Sci. USA 95, 14071–14075 (1998).

    Article  CAS  Google Scholar 

  24. Vogt, W., Zimmermann, B., Hesse, D. & Nolte, R. Activation of the fifth component of the human complement, C5, without cleavage, by methionine oxidising agents. Mol. Immunol. 29, 251–256 (1992).

    Article  CAS  Google Scholar 

  25. Hannappel, E. & van Kampen, M. Determination of thymosin β4 in human blood cells and serum. J. Chromat. 397, 279–285 (1987).

    Article  CAS  Google Scholar 

Download references

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.

Author information

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

Authors
  1. J.D. Young
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A.J. Lawrence
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A.G. MacLean
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B.P. Leung
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. I.B. McInnes
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B. Canas
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D.J.C. Pappin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. R.D. Stevenson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A.J. Lawrence.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/71002

This article is cited by

Search

Advanced 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