The prolactin-inducible-protein (PIP): A regulatory molecule in adaptive and innate immunity

Abstract

The Prolactin-inducible-protein (PIP)/Gross Cystic Disease Fluid Protein-15 (GCDFP-15) gene is highly expressed in salivary, lacrimal and sweat glands and the protein abundantly found in the secretions that originate from these glands; saliva, tears and sweat. PIP is thus considered to be strategically located at sites viewed as the first port of entry for invading organisms. PIP is also found over-expressed under abnormal and pathological conditions of the breast and prostate. The function of PIP has yet to be defined but it has been implicated to play a role in immunity, with respect to bacterial and viral infection, cancer and fertility. Despite such predictive functions, there is still no clear demonstration of an immunoregulatory role for PIP. In this review we will focus on accumulating evidence that suggests a role for PIP in both innate and adaptive immunity. Moreover, we will discuss recent evidence that defines a modulatory role for PIP with regards to a CD4+ T cell immune response, identifying for the first time, a critical role for PIP in effective cell-mediated immunity against an intracellular pathogen.

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Umadat, V. , Ihedioha, O. , Shiu, R. , Uzonna, J. and Myal, Y. (2013) The prolactin-inducible-protein (PIP): A regulatory molecule in adaptive and innate immunity. Open Journal of Immunology, 3, 210-217. doi: 10.4236/oji.2013.34026.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] Haagensen Jr., D.E. and Mazoujian, G. (1986) Diseases of the breast. W.B. Saunders, Philadelphia.
[2] Shiu, R.P. and Iwasiow, B.M. (1985) Prolactin-inducible proteins in human breast cancer cells. The Journal of Biological Chemistry, 260, 11307-11313.
[3] Murphy, L.C., Tsuyuki, D., Myal, Y. and Shiu, R.P. (1987) Isolation and sequencing of a cDNA clone for a prolactin-inducible protein (PIP). Regulation of PIP gene expression in the human breast cancer cell line, T-47D. The Journal of Biological Chemistry, 262, 15236-15241.
[4] Shiu, R.P., Murphy, L.C., Tsuyuki, D., Myal, Y., Lee-Wing, M. and Iwasiow, B. (1987) Biological actions of prolactin in human breast cancer. Recent Progress in Hormone Research, 43, 277-303.
[5] Caputo, E., Carratore, V., Ciullo, M., Tiberio, C., Mani, J.C., Piatier-Tonneau, D. and Guardiola, J. (1999) Biosynthesis and immunobiochemical characterization of gp17/ GCDFP-15. A glycoprotein from seminal vesicles and from breast tumors, in HeLa cells and in Pichia pastoris yeast. European Journal of Biochemistry, 265, 664-670. http://dx.doi.org/10.1046/j.1432-1327.1999.00758.x
[6] Akiyama, K. and Kimura, H. (1990) Isolation of a new actin-binding protein from human seminal plasma. Biochimica et Biophysica Acta, 1040, 206-210. http://dx.doi.org/10.1016/0167-4838(90)90077-S
[7] Schenkels, L.C., Schaller, J., Walgreen Weterings, E., Schadee Eestermans, I.L., Veerman, E.C. and Nieuw Amerongen, A.V. (1994) Identity of human extra parotid glycoprotein (EP-GP) with secretory actin binding protein (SABP) and its biological properties. Biological Chemistry Hoppe-Seyler, 375, 609-615. http://dx.doi.org/10.1515/bchm3.1994.375.9.609
[8] Myal, Y., Robinson, D.B., Iwasiow, B., Tsuyuki, D., Wong, P. and Shiu, R.P. (1991) The prolactin-inducible protein (PIP/GCDFP-15) gene: Cloning, structure and regulation. Molecular and Cellular Endocrinology, 80, 165-175. http://dx.doi.org/10.1016/0303-7207(91)90153-J
[9] Myal, Y. and Shiu, R.P.C. (2000) The physiology and pathology of an apocrine protein: The prolactin-inducible protein (PIP)/gross cystic disease fluid protein (GCDFP-15). Recent Research Developments in Endocrinology, pp. 321-335. Transworld Research Network, Trivandrum-8, India.
[10] Mazoujian, G., Pinkus, G.S., Davis, S. and Haagensen Jr., D.E., (1983) Immunohistochemistry of a gross cystic disease fluid protein (GCDFP-15) of the breast. A marker of apocrine epithelium and breast carcinomas with apocrine features. American Journal of Pathology, 110, 105-112.
[11] Myal, Y., Iwasiow, B., Yarmill, A., Harrison, E., Paterson, J.A. and Shiu, R.P. (1994) Tissue-specific androgen-inhibited gene expression of a submaxillary gland protein, a rodent homolog of the human prolactin-inducible protein/GCDFP-15 gene. Endocrinology, 135, 1605-1610. http://dx.doi.org/10.1210/en.135.4.1605
[12] Haagensen Jr., D.E., Mazoujian, G., Dilley, W.G., Pedersen, C.E., Kister, S.J. and Wells Jr., S.A. (1979) Breast gross cystic disease fluid analysis. I. Isolation and radioimmunoassay for a major component protein. Journal of the National Cancer Institute, 62, 239-247.
[13] Haagensen, C.D., Bodian, C. and Haagensen, D.E. (1981) Lobular neoplasia (lobular carcinoma in situ). In: Haagensen, C.D., Ed., Breast carcinoma: Risk and Detection. Philadelphia, W. B. Saunders, Philadelphia, 1981. p. 238.
[14] Clark, J.W., Snell, L., Shiu, R.P., Orr, F.W., Maitre, N., Vary, C.P., Cole, D.J. and Watson, P.H. (1999) The potential role for prolactin-inducible protein (PIP) as a marker of human breast cancer micrometastasis. British Journal of Cancer, 81, 1002-1008. http://dx.doi.org/10.1038/sj.bjc.6690799
[15] Blais, Y., Gingras, S., Haagensen, D.E., Labrie, F. and Simard, J. (1996) Interleukin-4 and interleukin-13 inhibit estrogen-induced breast cancer cell proliferation and stimulate GCDFP-15 expression in human breast cancer cells. Molecular and Cellular Endocrinology, 121, 11-18. http://dx.doi.org/10.1016/0303-7207(96)03843-9
[16] Hassan, M.I., Waheed, A., Yadav, S., Singh, T.P. and Ahmad, F. (2009) Prolactin-inducible-protein in cancer, fertility and immunoregulation: Structure, function and its clinical implications. Cellular and Molecular Life Sciences, 66, 447-459. http://dx.doi.org/10.1007/s00018-008-8463-x
[17] Rathman, W.M., Van Zeyl, M.J., Van den Keybus, P.A., Bank, R.A., Veerman, E.C. and Nieuw Amerongen, A.V. (1989) Isolation and characterization of three non-mucinous human salivary proteins with affinity for hydroxyapatite. Journal de Biologie Buccale, 17, 199-208.
[18] Rathman, W.M., Van Zeyl, M.J., van den Keijbus, P.A., Veerman, E.C. and Nieuw Amerongen, A.V. (1990) Comparison of a salivary 14 kD protein displaying cysteine proteinase inhibitory activity with other salivary cystatins. Journal de Biologie Buccale, 18, 9-18.
[19] Caputo, E., Manco, G., Mandrich, L. and Guardiola, J. (2000) A novel aspartyl proteinase from apocrine epithelia and breast tumors. Journal de Biologie Buccale, 275, 7935-7941. http://dx.doi.org/10.1074/jbc.275.11.7935
[20] Miller, M., Jaskolski, M., Rao, J.K., Leis, J. and Wlodawer, A. (1989) Crystal structure of a retroviral protease proves relationship to aspartic protease family. Nature, 337, 576-579. http://dx.doi.org/10.1038/337576a0
[21] Anderson, S.T., Barclay, J.L., Fanning, K.J., Kusters, D.H., Waters, M.J. and Curlewis, J.D. (2006) Mechanisms underlying the diminished sensitivity to prolactin negative feedback during lactation: Reduced STAT5 signaling and up-regulation of cytokine-inducible SH2 domain-containing protein (CIS) expression in tuberoinfundibular dopaminergic neurons. Endocrinology, 147, 1195-1202. http://dx.doi.org/10.1210/en.2005-0905
[22] Chiu, W.W. and Chamley, L.W. (2003) Human seminal plasma prolactin-inducible protein is an immunoglobulin G-binding protein. Journal of Reproductive Immunology, 60, 97-111. http://dx.doi.org/10.1016/S0165-0378(03)00084-6
[23] Kumar, S., Tomar, A.K., Singh, S., Saraswat, M., Singh, S., Singh, T.P. and Yadav, S. (2012) Human serum albumin as a new interacting partner of prolactin-inducible-protein in human seminal plasma. International Journal of Biological Macromolecules, 50, 317-322. http://dx.doi.org/10.1016/j.ijbiomac.2011.12.015
[24] Yoshida, M., Kaneko, M., Kurachi, H., and Osawa, M. (2001) Identification of two rodent genes encoding homologues to seminal vesicle autoantigen: A gene family including the gene for prolactin-inducible protein. Biochemical and Biophysical Research Communications, 281, 94-100. http://dx.doi.org/10.1006/bbrc.2001.4311
[25] Levinson, W. (2010) Review of Medical Microbiology and Immunology. 11th Edition, McGraw-Hill, New York.
[26] Paul, W.E. (2008) Fundamental Immunology. 6th Edition, Lippincott Williams & Wilkins, Philadelphia.
[27] Janeway Jr., C.A. and Medzhitov, R. (2002) Innate immune recognition. Annual Review of Immunology, 20, 197-216. http://dx.doi.org/10.1146/annurev.immunol.20.083001.084359
[28] Schenkels, L.C., Walgreen-Weterings, E., Oomen, L.C., Bolscher, J.G., Veerman, E.C., and Nieuw Amerongen, A.V. (1997) In vivo binding of the salivary glycoprotein EP-GP (identical to GCDFP-15) to oral and non-oral bacteria detection and identification of EP-GP binding species. Biological Chemistry, 378, 83-88. http://dx.doi.org/10.1515/bchm.1997.378.2.83
[29] Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K. and Walter, P. (2002) The adaptive immune system. In: Molecular Biology of the Cell, Garland Science, New York. http://www.ncbi.nlm.nih.gov/books/NBK21070/
[30] Warger, T., Osterloh, P., Rechtsteiner, G., Fassbender, M., Heib, V., Schmid, B., Schmitt, E., Schild, H. and Radsak, M.P. (2006) Synergistic activation of dendritic cells by combined toll-like receptor ligation induces superior CTL responses in vivo. Blood, 108, 544-550. http://dx.doi.org/10.1182/blood-2005-10-4015
[31] Zhou, W. and Konig, R. (2003) T cell receptor-independent CD4 signalling: CD4-MHC class II interactions regulate intracellular calcium and cyclic AMP. Cell Signaling, 15, 751-762. http://dx.doi.org/10.1016/S0898-6568(03)00037-8
[32] Klatzmann, D., Champagne, E., Chamaret, S., Gruest, J., Guetard, D., Hercend, T., Gluckman, J.C. and Montagnier, L. (1984) T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV. Nature, 312, 767-768. http://dx.doi.org/10.1038/312767a0
[33] Maddon, P.J., Dalgleish, A.G., McDougal, J.S., Clapham, P.R., Weiss, R.A. adn Axel, R. (1986) The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain. Cell, 47, 333-348. http://dx.doi.org/10.1016/0092-8674(86)90590-8
[34] McDougal, J.S., Nicholson, J.K., Cross, G.D., Cort, S.P., Kennedy, M.S. and Mawle, A.C. (1986) Binding of the human retrovirus HTLV-III/LAV/ARV/HIV to the CD4 (T4) molecule: Conformation dependence, epitope mapping, antibody inhibition, and potential for idiotypic mimicry. The Journal of Immunology, 137, 2937-2944.
[35] Autiero, M., Gaubin, M., Mani, J.C., Castejon, C., Martin, M., El, M.S., Guardiola, J. and Piatier-Tonneau, D. (1997) Surface plasmon resonance analysis of gp17, a natural CD4 ligand from human seminal plasma inhibiting human immunodeficiency virus type-1 gp120-mediated syncytium formation. European Journal of Biochemistry, 245, 208-213. http://dx.doi.org/10.1111/j.1432-1033.1997.00208.x
[36] Gaubin, M., Autiero, M., Basmaciogullari, S., Metivier, D., Mis, H.Z., Culerrier, R., Oudin, A., Guardiola, J. and Piatier-Tonneau, D. (1999) Potent inhibition of CD4/TCR-mediated T cell apoptosis by a CD4-binding glycoprotein secreted from breast tumor and seminal vesicle cells. Journal of Immunology, 162, 2631-2638.
[37] Autiero, M., Abrescia, P. and Guardiola, J. (1991) Interaction of seminal plasm proteins with cell surface antigens: Presence of a CD4-binding glycoprotein in human seminal plasma. Experimental Cell Research, 197, 268-271. http://dx.doi.org/10.1016/0014-4827(91)90432-T
[38] Lorenzen, J., Lewis, C.E., McCracken, D., Horak, E., Greenall, M. and McGee, J.O. (1991) Human tumour-associated NK cells secrete increased amounts of interferon-gamma and interleukin-4. British Journal of Cancer, 64, 457-462. http://dx.doi.org/10.1038/bjc.1991.331
[39] Autiero, M., Cammarota, G., Friedlein, A., Zulauf, M., Chiappetta, G., Dragone, V. and Guardiola, J. (1995) A 17-kDa CD4-binding glycoprotein present in human seminal plasma and in breast tumor cells. European Journal of Immunology, 25, 1461-1464. http://dx.doi.org/10.1002/eji.1830250550
[40] Chiu, W.W. and Chamley, L.W. (2002) Antibody-binding proteins in human seminal plasma. American Journal of Reproductive Immunology, 48, 269-274. http://dx.doi.org/10.1034/j.1600-0897.2002.01122.x
[41] Lin, X., Koelsch, G., Wu, S., Downs, D., Dashti, A. and Tang, J. (2000) Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proceedings of National. Academy of Sciences of the United States of America, 97, 1456-1460. http://dx.doi.org/10.1073/pnas.97.4.1456
[42] Van Seventer, G.A., Shimizu, Y., Horgan, K.J. and Shaw, S. (1990) The LFA-1 ligand ICAM-1 provides an important costimulatory signal for T cell receptor-mediated activation of resting T cells. Journal of Immunology, 144, 4579-4586.
[43] Matsuyama, T., Yamada, A., Kay, J., Yamada, K.M., Akiyama, S.K., Schlossman, S.F. and Morimoto, C. (1989) Activation of CD4 cells by fibronectin and anti-CD3 antibody. A synergistic effect mediated by the VLA-5 fibronectin receptor complex. Journal of Experimental Medicine, 170, 1133-1148. http://dx.doi.org/10.1084/jem.170.4.1133
[44] Wick, M.R., Lillemoe, T.J., Copland, G.T., Swanson, P.E., Manivel, J.C. and Kiang, D.T. (1989) Gross cystic disease fluid protein-15 as a marker for breast cancer: Immunohistochemical analysis of 690 human neoplasms and comparison with alpha-lactalbumin. Human Pathology, 20, 281-287. http://dx.doi.org/10.1016/0046-8177(89)90137-8
[45] Basset, P., Bellocq, J.P., Wolf, C., Stoll, I., Hutin, P., Limacher, J.M., Podhajcer, O.L., Chenard, M.P., Rio, M.C. and Chambon, P. (1990) A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas. Nature, 348, 699-704. http://dx.doi.org/10.1038/348699a0
[46] Chauhan, S.S., Goldstein, L.J. and Gottesman, M.M. (1991) Expression of cathepsin L in human tumors. Cancer Research, 51, 1478-1481.
[47] Naderi, A. and Meyer, M. (2012) Prolactin-induced protein mediates cell invasion and regulates integrin signaling in estrogen receptor-negative breast cancer. Breast Cancer Research, 14, R111. http://dx.doi.org/10.1186/bcr3232
[48] Schaller, M., Korting, H.C., Borelli, C., Hamm, G. and Hube, B. (2005) Candida albicans-secreted aspartic proteinases modify the epithelial cytokine response in an in vitro model of vaginal candidiasis. Infection and Immunity, 73, 2758-2765. http://dx.doi.org/10.1128/IAI.73.5.2758-2765.2005
[49] Hassan, M.I., Bilgrami, S., Kumar, V., Singh, N., Yadav, S., Kaur, P. and Singh, T.P. (2008) Crystal structure of the novel complex formed between zinc α2-glycoprotein (ZAG) and prolactin-inducible protein (PIP) from human seminal plasma. Journal of Molecular Biology, 384, 663-672. http://dx.doi.org/10.1016/j.jmb.2008.09.072
[50] Blanchard, A., Nistor, A., Castaneda, F.E., Martin, D., Hicks, G.G., Amara, F., Shiu, R.P. and Myal, Y. (2009) Generation and initial characterization of the prolactin-inducible protein (PIP) null mouse: Accompanying global changes in gene expression in the submandibular gland. Canadian Journal of Physiology and Pharmacology, 87, 859-872. http://dx.doi.org/10.1139/Y09-077
[51] Windass, J.D., Mullins, J.J., Beecroft, L.J., George, H., Meacock, P.A., Williams, B.R. and Brammar, W.J. (1984) Molecular cloning of cDNAs from androgen-independent mRNA species of DBA/2 mouse sub-maxillary glands. Nucleic Acids Research, 12, 1361-1376. http://dx.doi.org/10.1093/nar/12.3.1361
[52] Lee, B., Bowden, G.H. and Myal, Y. (2002) Identification of mouse submaxillary gland protein in mouse saliva and its binding to mouse oral bacteria. Archives of Oral Biology, 47, 327-332. http://dx.doi.org/10.1016/S0003-9969(01)00113-3
[53] Nistor, A. (2008) Investigations into the role of mPIP, the mouse homologue of hPIP/GCDFP-15, in innate host defense. Master Thesis, University of Manitoba, Winnipeg.

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