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© The Rockefeller University Press, 0022-1007/1999/6/1783/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 11, June 7, 1999 1783-1789

Articles

Thioredoxin, a Redox Enzyme Released in Infection and Inflammation, Is a Unique Chemoattractant for Neutrophils, Monocytes, and T Cells

Riccardo Bertini*, O.M. Zack Howard{ddagger}, Hui-Fang Dong{ddagger}, Joost J. Oppenheim{ddagger}, Cinzia Bizzarri§, Rita Sergi*, Gianfranco Caselli*, Sabrina Pagliei*, Brie Romines||, Jennifer A. Wilshire||, Manuela Mengozzi||, Hajime Nakamura, Junji Yodoi, Klas Pekkari**, Ramanathan Gurunath**, Arne Holmgren**, Leonore A. Herzenberg||, Leonard A. Herzenberg||, and Pietro Ghezzi||

From the * Dompé Research Center, 67100 L'Aquila, Italy; the {ddagger} Laboratory of Molecular Immunoregulation, National Cancer Institute-Frederick Cancer Research Development Center, Frederick, MD 21702; § Consorzio Biolaq, 67100 L'Aquila, Italy; the || Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305; the Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606, Japan; and the ** Medical Nobel Institute for Biochemistry, Karolinska Institutet, S-17177 Stockholm, Sweden

Thioredoxin (Trx) is a ubiquitous intracellular protein disulfide oxidoreductase with a CXXC active site that can be released by various cell types upon activation. We show here that Trx is chemotactic for monocytes, polymorphonuclear leukocytes, and T lymphocytes, both in vitro in the standard micro Boyden chamber migration assay and in vivo in the mouse air pouch model. The potency of the chemotactic action of Trx for all leukocyte populations is in the nanomolar range, comparable with that of known chemokines. However, Trx does not increase intracellular Ca2+ and its activity is not inhibited by pertussis toxin. Thus, the chemotactic action of Trx differs from that of known chemokines in that it is G protein independent. Mutation of the active site cysteines resulted in loss of chemotactic activity, suggesting that the latter is mediated by the enzyme activity of Trx. Trx also accounted for part of the chemotactic activity released by human T lymphotropic virus (HTLV)-1–infected cells, which was inhibited by incubation with anti-Trx antibody. Since Trx production is induced by oxidants, it represents a link between oxidative stress and inflammation that is of particular interest because circulating Trx levels are elevated in inflammatory diseases and HIV infection.

Key Words: chemotaxis • thioredoxin • HTLV-1 • migration

Address correspondence to Pietro Ghezzi, Stanford University Department of Genetics, Beckman Center B-007, 300 Pasteur Dr., Stanford, CA 94305-5318. Phone: 650-723-7149; Fax: 650-725-8564; E-mail: ghezzi{at}stanford.edu

This work was partially supported by the contract "Programma Nazionale di Ricerca e Formazione sui Farmaci (Seconda Fase), Tema I", granted by the Italian Ministry of University and Scientific and Technological Research; by National Institutes of Health (NIH) grant CA42509 (to Leonard A. Herzenberg); and by the Swedish Cancer Society (A. Holmgren). O.M.Z. Howard and H.-F. Dong are funded in part by NCI, NIH contract NO1-CO-56000.

Abbreviations used: GST, glutathione-S-transferase; HTLV, human T lymphotropic virus; MCP, monocyte chemotactic protein; PT, pertussis toxin; Trx, thioredoxin.


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