Animals; Cells, Cultured; Comparative Study; Enzyme Induction/drug effects; Fibroblasts/*metabolism; Nitric Oxide/*metabolism; Nitric Oxide Synthase/*metabolism; Nitric Oxide Synthase Type II; Peptide Fragments/metabolism/*pharmacology; Prolactin/metabolism/*pharmacology; Rats; Rats, Sprague-Dawley; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.
Abstract :
[en] Prolactin (PRL), originally associated with milk secretion, is now known to possess a wide variety of biological actions and diverse sites of production beyond the pituitary. Proteolytic cleavage is a common post-translational modification that can either activate precursor proteins or confer upon the peptide fragment unique biological actions not exerted by the parent molecule. Recent studies have demonstrated that the 16-kDa N-terminal proteolytic cleavage product of PRL (16K-PRL) acts as a potent inhibitor of angiogenesis. Despite previous demonstrations of 16K-PRL production in vivo, biological functions beyond its antiangiogenic actions remain unknown. Here we show that 16K-PRL, but not full-length PRL, acts to promote the expression of the inducible isoform of nitric oxide synthase (iNOS) and nitric oxide (*NO) production by pulmonary fibroblasts and alveolar type II cells with potency comparable with the proinflammatory cytokines interleukin-1beta, interferon gamma, and tumor necrosis factor alpha. The differential effect of 16K-PRL versus PRL occurs through a receptor distinct from known PRL receptors. Additionally, pulmonary fibroblasts express the PRL gene and endogenously produce 16K-PRL, suggesting that this pathway may serve both autocrine and paracrine roles in the regulation of *NO production. These results reveal that proteolytic cleavage of PRL confers upon this classical hormone potent iNOS inducing activity, suggesting its role in inflammatory/immune processes.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Corbacho, A. M.
Nava, G.
Eiserich, J. P.
Noris, G.
Macotela, Y.
Struman, Ingrid ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire
Martinez De La Escalera, G.
Freeman, B. A.
Clapp, C.
Language :
English
Title :
Proteolytic cleavage confers nitric oxide synthase inducing activity upon prolactin
Publication date :
2000
Journal title :
Journal of Biological Chemistry
ISSN :
0021-9258
eISSN :
1083-351X
Publisher :
American Society for Biochemistry and Molecular Biology, United States - Maryland
Ben-Jonathan, N., Mershon, J. L., Allen, D. L., and Steinmetz, R. W. (1996) Endocr. Rev. 17, 639-669
Bole-Feysot, C., Goffin, V., Edery, M., Binart, N., and Kelly, P. A. (1998) Endocr. Rev. 19, 225-268
Clapp, C., López-Gómez, F. J., Nava, G., Corbacho, A., Torner, L., Macotela, Y., Dueñas, Z., Noris, G., Acosta, E., Garay, E., and Martínez de la Escalera, G. (1998) J. Endocrinol. 158, 137-144
Bazan, J. F. (1989) Biochem. Biophys. Res. Commun. 164, 788-795
Cosman, D., Lyman, S. D., Idzerda, R. L., Beckman, M. P., Park, L. S., Goodwin, R. G., and March. C. J. (1990) Trends Biochem. Sci. 15, 265-270
Chikanza, I. C. (1999) Ann. N. Y. Acad. Sci. 876, 119-130
Nathan, C. (1997) J. Clin. Invest. 100, 2417-2423
Meli, R., Raso, G. M., Gualillo, O., Pacilio, M., and Di Carlo, R. (1997) Life Sci. 61, 1395-1403
Ferrara, N., Clapp, C., and Weiner, R. (1991) Endocrinology 129, 896-900
Clapp, C., Martial, J. A., Guzman, R. C., Rentier-Delrue, F., and Weiner, R. I. (1993) Endocrinology 133, 1292-1299
Struman, I., Bentzien, F., Lee, H., Mainfroid. V., D'Angelo, G., Goffin, V., Weiner, R. I., and Martial, J. A. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 1246-1251
Sinha, Y. N. (1995) Endocr. Rev. 16, 354-369
Torner, L., Mejía, S., López-Gómez, F. J., Quintanar, A., Martínez de la Escalera, G., and Clapp, C. (1995) Endocrinology 136, 5454-5460
D'Angelo, G., Martini, J. F., Iiri, T., Fantl, W. J., Martial, J., and Weiner, R. I. (1999) Mol. Endocrinol. 13, 692-704
Imai, T., Hirata, Y., Kanno, K., and Marumo, F. (1994) J. Clin. Invest. 93, 543-549
O'Reilly, M. S., Holmgren, L., Shing, Y., Chen, C., Rosenthal, R. A., Moses, M., Lane, W. S., Cao, Y., Sage, E. H., and Folkman, J. (1994) Cell 79, 315-328
O'Reilly, M. S., Boehm, T., Shing, Y., Fukai, N., Vasios, G., Lane, W. S., Flynn, E., Birkhead, J. R., Olsen, B. R., and Folkman, J. (1997) Cell 88, 277-285
Moss, M. L., Jin, S. L., Becherer, J. D., Bickett, D. M., Burkhart, W., Chen, W. J., Hassler, D., Leesnitzer, M. T., McGeehan, G., Milla, M., Moyer, M., Rocque, W., Seaton, T., Schoenen, F., Warner, J., and Willard, D. (1997) J. Neuroimmunol. 72, 127-129
Thornberry, N. A., Bull, H. G., Calaycay, J. R., Chapman, K. T., Howard, A. D., Kostura, M. J., Miller, D. K., Molineaux, S. M., Weidner, J. R., Aunins, J., et al. (1992) Nature 356, 768-774
Nagase, H., and Woessner, J. F., Jr. (1999) J. Biol. Chem. 274, 21491-21494
Caniggia, I., Tseu, I., Han, R. N., Smith, B. T., Transwell, K., and Post, M. (1991) Am. J. Physiol. 261, L424-L433
Travo, P., Barret, G., and Burnstock, G. (1980) Blood Vessels 17, 110-116
Gutierrez, H. H., Pitt, B. R., Schwarz, M., Watkins, S. C., Lowenstein, C., Caniggia, I., Chumley, P., and Freeman, B. A. (1995) Am. J. Physiol. 268, L501-L508
Torner, L., Nava, G., Dueñas, Z., Corbacho, A., Mejía, S., López, F., Cajero, M., Martínez de la Escalera, G., and Clapp, C. (1999) J. Endocrinol. 161, 423-432
Clapp, C., and Weiner, R. I. (1992) Endocrinology 130, 1380-1386
Munson, P. J., and Rodbard, D. (1980) Anal. Biochem. 107, 220-259
Raso, G. M., Meli, R., Gualillo, O., Pacilio, M., and Di Carlo, R. (1999) J. Neurochem. 73, 2272-2277
Jorens, P. G., Van Overveld, F. J., Vermiere, P. A., Bult, H., and Herman, A. G. (1992) Eur. J. Pharmacol. 224, 7-12
Asano, K., Chee, C. B. E., Gaston, B., Lilly, C. M., Gerard, C., Drazen, J. M., and Stamler, J. S. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 10089-10093
Moncada, S., Palmer, R. M. J., and Higgs, E. A. (1991) Pharmacol. Rev. 43, 109-142
Gaston, B., Drazen, J. M., Loscalzo, J., and Stamler, J. S. (1994) Am. J. Respir. Crit. Care Med. 149, 538-551
van der Vliet, A., Eiserich, J. P., Shigenaga, M. K., and Cross, C. E. (1999) Am. J. Respir. Crit. Care Med. 159, 1-9