Abstract
Cysteinyl leukotrienes are established mediators of bronchial asthma and have agonist roles analogous to those of histamine in allergic rhinitis. We now know that the substance originally termed slow-reacting substance of anaphylaxis was composed of three cysteinyl leukotrienes that act in the inflammatory response via receptors on smooth muscle and on bone marrow–derived inflammatory cells. K. Frank Austen describes the work culminating in the identification, biosynthesis and functional characterization of these moieties.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
References
Austen, K.F. & Brocklehurst, W.E. Anaphylaxis in chopped guinea pig lung. I. Effect of peptidase substrates and inhibitors. J. Exp. Med. 113, 521–539 (1961).
Austen, K.F. & Brocklehurst, W.E. Anaphylaxis in chopped guinea pig lung. II. Enhancement of the anaphylactic release of histamine and slow reacting substance by certain dibasic aliphatic acids and inhibition by monobasic fatty acids. J. Exp. Med. 113, 541–557 (1961).
Austen, K.F. & Brocklehurst, W.E. Anaphylaxis in chopped guinea pig lung. III. Effect of carbon monoxide, cyanide, salicylaldoxine, and ionic strength. J. Exp. Med. 114, 29–42 (1961).
Stechschulte, D.J., Austen, K.F. & Bloch, K.J. Antibodies involved in antigen-induced release of slow reacting substance of anaphylaxis (SRS-A) in the guinea pig and rat. J. Exp. Med. 125, 127–147 (1967).
Ishizaka, T., Ishizaka, K., Orange, R.P. & Austen, K.F. The capacity of human immunoglobulin E to mediate the release of histamine and slow reacting substance of anaphylaxis (SRS-A) from monkey lung. J. Immunol. 104, 335–343 (1970).
Orange, R.P., Murphy, R.C., Karnovsky, M.L. & Austen, K.F. The physicochemical characteristics and purification of slow reacting substance of anaphylaxis. J. Immunol. 110, 760–770 (1973).
Murphy, R.C., Hammarstrom, S. & Samuelsson, B. Leukotriene C: a slow-reacting substance from murine mastocytoma cells. Proc. Natl. Acad. Sci. USA 76, 4275–4279 (1979).
Marfat, A. & Corey, E.J. Synthesis and structure elucidation of leukotrienes. in Advances in Prostaglandin, Thromboxane, and Leukotriene Research Vol. 14 (eds. Pike, J.E. & Morton, D.R. Jr.) 155–228 (Raven Press, New York, 1985).
Lewis, R.A. et al. Identification of the C(6)-S-conjugate of leukotriene A with cysteine as a naturally occurring slow reacting substance of anaphylaxis (SRS-A). Importance of the 11-cis-geometry for biological activity. Biochem. Biophys. Res. Commun. 96, 271–277 (1980).
Lee, T.H., Austen, K.F., Corey, E.J. & Drazen, J.M. Leukotriene E4-induced airway hyperresponsiveness of guinea pig tracheal smooth muscle to histamine and evidence for three separate sulfidopeptide leukotriene receptors. Proc. Natl. Acad. Sci. USA 81, 4922–4925 (1984).
Lynch, K.R. et al. Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature 399, 789–793 (1999).
Soter, N.A., Lewis, R.A., Corey, E.J. & Austen, K.F. Local effects of synthetic leukotrienes (LTC4, LTD4, LTE4 and LTB4) in human skin. J. Invest. Dermatol. 80, 115–119 (1983).
Weiss, J.W. et al. Bronchoconstrictor effects of leukotriene C in humans. Science 216, 196–198 (1982).
Drazen, J.M., Israel, E. & O'Byrne, P. Treatment of asthma with drugs modifying the leukotriene pathway. N. Engl. J. Med. 340, 197–206 (1999).
Bisgaard, H. Leukotriene modifiers in pediatric asthma management. Pediatrics 107, 381–390 (2001).
Yoshimoto, T., Soberman, R.J., Spur, B. & Austen, K.F. Properties of highly purified leukotriene C4 synthase of guinea pig lung. J. Clin. Invest. 81, 866–871 (1988).
Lam, B.K., Penrose, J.F., Freeman, G.J. & Austen, K.F. Expression cloning of a cDNA for human leukotriene C4 synthase, a novel integral membrane protein conjugating reduced glutathione to leukotriene A4 . Proc. Natl. Acad. Sci. USA 91, 7663–7667 (1994).
Penrose, J.F. et al. Molecular cloning of the gene for human leukotriene C4 synthase: organization, nucleotide sequence, and chromosomal localization to 5q35. J. Biol. Chem. 271, 11356–11361 (1996).
Hsieh, F.H. et al. T helper cell type 2 cytokines coordinately regulate immunoglobulin E-dependent cysteinyl leukotriene production by human cord blood-derived mast cells: profound induction of leukotriene C4 synthase expression by interleukin 4. J. Exp. Med. 193, 123–133 (2001).
Schmidt-Krey, I. et al. Human leukotriene C4 synthase at 4.5 Å resolution in projection. Structure 12, 2009–2014 (2004).
Ago, H. et al. Crystal structure of LTC4 synthase, the membrane protein for cysteinyl leukotriene biosynthesis. Nature 448, 609–612 (2007).
Kanaoka, Y. et al. Attenuated zymosan-induced peritoneal vascular permeability and IgE-dependent passive cutaneous anaphylaxis in mice lacking leukotriene C4 synthase. J. Biol. Chem. 276, 22608–22613 (2001).
Maekawa, A., Austen, K.F. & Kanaoka, Y. Targeted gene disruption reveals the role of cysteinyl leukotriene 1 receptor in the enhanced vascular permeability of mice undergoing acute inflammatory responses. J. Biol. Chem. 277, 20820–20824 (2002).
Beller, T.C. et al. Targeted gene disruption reveals the role of the cysteinyl leukotriene 2 receptor in increased vascular permeability and in bleomycin-induced pulmonary fibrosis in mice. J. Biol. Chem. 279, 46129–46134 (2004).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Austen, K. The cysteinyl leukotrienes: Where do they come from? What are they? Where are they going?. Nat Immunol 9, 113–115 (2008). https://doi.org/10.1038/ni0208-113
Issue Date:
DOI: https://doi.org/10.1038/ni0208-113
This article is cited by
-
Leukotrienes promote stem cell self-renewal and chemoresistance in acute myeloid leukemia
Leukemia (2022)
-
Oxygenated lipid signaling in tumor-associated macrophages—focus on colon cancer
Cancer and Metastasis Reviews (2018)