Pregnancy-associated Changes in the Glycosylation of Tamm-Horsfall Glycoprotein

Tamm-Horsfall glycoprotein (THP) is a major glycoprotein associated with human urine that binds pro-inflammatory cytokines and also inhibits in vitro T cell proliferation induced by specific antigens. THP derived from human pregnancy urine (designated uromodulin) has previously been shown to be 13-fold more effective as an inhibitor of antigen-induced T cell proliferation than THP obtained from other sources. Structural analysis of human THP and uromodulin has for the first time revealed that these glycoproteins areO-glycosylated. THP from nonpregnant females and males expresses primarily core 1 type O-glycans terminated with either sialic acid or fucose but not the sialyl Lewisxepitope. By contrast, the O-glycans linked to uromodulin include unusual core 2 type glycans terminated with one, two, or three sialyl Lewisx sequences. The specific association of these unusual carbohydrate sequences with uromodulin could explain its enhanced immunomodulatory effects compared with THP obtained from males and nonpregnant females. Analysis of THP from one of the pregnant females 2 months postpartum showed a reversion of theO-glycan profile to that found for a non-pregnant female. These data suggest that the glycosylation state of uromodulin could be under the regulation of steroidal hormones produced during pregnancy. The significant physiological implications of these observations are discussed.

[1]  J. Hoyer,et al.  Pathophysiology of Tamm-Horsfall protein. , 1979, Kidney international.

[2]  G. Meschia,et al.  Human Chorionic Gonadotropin: Its Possible Role in Maternal Lymphocyte Suppression , 1973, Science.

[3]  M. Fukuda,et al.  Glycobiology : a practical approach , 1993 .

[4]  D. Herbert,et al.  Progesterone--specific binding sites in the kidney of the female baboon. , 1984, The Journal of urology.

[5]  F. di Silverio,et al.  Human kidney steroid receptors. , 1976, Journal of steroid biochemistry.

[6]  I. Ørskov,et al.  TAMM-HORSFALL PROTEIN OR UROMUCOID IS THE NORMAL URINARY SLIME THAT TRAPS TYPE 1 FIMBRIATED ESCHERICHIA COLI , 1980, The Lancet.

[7]  J. Kamerling,et al.  Glycosylation sites and site-specific glycosylation in human Tamm-Horsfall glycoprotein. , 1999, Glycobiology.

[8]  C. Tsai,et al.  Tamm-Horsfall glycoprotein (THG) purified from normal human pregnancy urine increases phagocytosis, complement receptor expressions and arachidonic acid metabolism of polymorphonuclear neutrophils. , 1992, Immunopharmacology.

[9]  I. Tamm,et al.  A MUCOPROTEIN DERIVED FROM HUMAN URINE WHICH REACTS WITH INFLUENZA, MUMPS, AND NEWCASTLE DISEASE VIRUSES , 1951, The Journal of experimental medicine.

[10]  J. Decker,et al.  The lectin-like interaction between recombinant tumor necrosis factor and uromodulin. , 1988, The Journal of biological chemistry.

[11]  J. Decker,et al.  Uromodulin: a unique 85-kilodalton immunosuppressive glycoprotein isolated from urine of pregnant women. , 1985, Science.

[12]  Gary F. Clark,et al.  Gender-specific Glycosylation of Human Glycodelin Affects Its Contraceptive Activity* , 1996, The Journal of Biological Chemistry.

[13]  M. Tiemeyer,et al.  Carbohydrate ligands for endothelial-leukocyte adhesion molecule 1. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[14]  P. Wingfield,et al.  Native cytokines do not bind to uromodulin (Tamm‐Horsfall glycoprotein) , 1988, FEBS letters.

[15]  A. Donald,et al.  A blood group Sda-active pentasaccharide isolated from Tamm-Horsfall urinary glycoprotein. , 1983, Biochemical and biophysical research communications.

[16]  K. Hård,et al.  The Asn-linked carbohydrate chains of human Tamm-Horsfall glycoprotein of one male. Novel sulfated and novel N-acetylgalactosamine-containing N-linked carbohydrate chains. , 1992, European journal of biochemistry.

[17]  J. Decker,et al.  Evidence that recombinant IL 1 alpha exhibits lectin-like specificity and binds to homogeneous uromodulin via N-linked oligosaccharides. , 1987, Journal of immunology.

[18]  Petr Malý,et al.  The α(1,3)Fucosyltransferase Fuc-TVII Controls Leukocyte Trafficking through an Essential Role in L-, E-, and P-selectin Ligand Biosynthesis , 1996, Cell.

[19]  J. Kamerling,et al.  Sulfated di-, tri- and tetraantennary N-glycans in human Tamm-Horsfall glycoprotein. , 1998, European journal of biochemistry.

[20]  L. Lasky,et al.  Sulphation requirement for GlyCAM-1, an endothelial ligand for L-selectin , 1993, Nature.

[21]  R. Cummings,et al.  Fractionation of asparagine-linked oligosaccharides by serial lectin-Agarose affinity chromatography. A rapid, sensitive, and specific technique. , 1982, The Journal of biological chemistry.

[22]  S. Watson,et al.  The three members of the selectin receptor family recognize a common carbohydrate epitope, the sialyl Lewis(x) oligosaccharide , 1992, The Journal of cell biology.

[23]  Donald J. Nevins,et al.  A method for the analysis of sugars in plant cell-wall polysaccharides by gas-liquid chromatography , 1967 .

[24]  A. Kobata,et al.  Detection of Novel Carbohydrate Binding Activity of Interleukin-1* , 1999, The Journal of Biological Chemistry.

[25]  Brian Seed,et al.  PSGL-1 recognition of P-selectin is controlled by a tyrosine sulfation consensus at the PSGL-1 amino terminus , 1995, Cell.

[26]  S. Tsuboi,et al.  Core 2 oligosaccharide biosynthesis distinguishes between selectin ligands essential for leukocyte homing and inflammation. , 1998, Immunity.

[27]  A. Afonso Isolation and characterisation of glycopeptides from digests of human Tamm-Horsfall glycoprotein. , 1981, Carbohydrate research.

[28]  J. Decker,et al.  IL-2, a lectin with specificity for high mannose glycopeptides. , 1989, Journal of immunology.

[29]  C. Hobel,et al.  Plasma estrone, estradiol, estriol, progesterone, and 17-hydroxyprogesterone in human pregnancy. I. Normal pregnancy. , 1972, American journal of obstetrics and gynecology.

[30]  Richard D. Cummings,et al.  Tyrosine Sulfation of P-selectin Glycoprotein Ligand-1 Is Required for High Affinity Binding to P-selectin (*) , 1995, The Journal of Biological Chemistry.

[31]  D. Stites,et al.  Human Chorionic Gonadotropin: Effects of Crude and Purified Preparations on Lymphocyte Responses to Phytohemagglutinin and Allogeneic Stimulation , 1975, The Journal of Immunology.

[32]  I. Tamm,et al.  Characterization and Separation of an Inhibitor of Viral Hemagglutination Present in Urine , 1950, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[33]  Chi‐yuen Wang Shear Elastic Constant C44 and Phase Transformation of KCl , 1973, Nature.

[34]  A. Dell,et al.  Structure of sialylated fucosyl lactosaminoglycan isolated from human granulocytes. , 1984, The Journal of biological chemistry.

[35]  J. Lowe,et al.  ELAM-1-dependent cell adhesion to vascular endothelium determined by a transfected human fucosyltransferase cDNA , 1990, Cell.

[36]  J. Kamerling,et al.  The abundance of additional N-acetyllactosamine units in N-linked tetraantennary oligosaccharides of human Tamm-Horsfall glycoprotein is a donor-specific feature. , 1998, Glycobiology.

[37]  M. Fukuda,et al.  Expression cloning of a cDNA encoding UDP-GlcNAc:Gal beta 1-3-GalNAc-R (GlcNAc to GalNAc) beta 1-6GlcNAc transferase by gene transfer into CHO cells expressing polyoma large tumor antigen. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[38]  S. Hakomori,et al.  CD62 and endothelial cell-leukocyte adhesion molecule 1 (ELAM-1) recognize the same carbohydrate ligand, sialyl-Lewis x. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[39]  A. Birch‐Andersen,et al.  Comparison of Escherichia coli fimbrial antigen F7 with type 1 fimbriae , 1980, Infection and immunity.

[40]  J. Bates,et al.  Uromodulin (Tamm-Horsfall protein) is a leukocyte adhesion molecule. , 1994, Biochemical and biophysical research communications.

[41]  E. Chen,et al.  Identification of human uromodulin as the Tamm-Horsfall urinary glycoprotein. , 1987, Science.

[42]  R. Mattaliano,et al.  Uromodulin (Tamm-Horsfall glycoprotein): a renal ligand for lymphokines. , 1987, Science.

[43]  S. Contractor,et al.  Effect of human chorionic somatomammotrophin and human chorionic gonadotrophin on phytohaemagglutinin-induced lymphocyte transformation. , 1973, Nature: New biology.

[44]  A. Mizoguchi,et al.  Changes in asparagine-linked sugar chains of human promyelocytic leukemic cells (HL-60) during monocytoid differentiation and myeloid differentiation. Decrease of high-molecular-weight oligosaccharides in acidic fraction. , 1984, The Journal of biological chemistry.

[45]  F. Gaeta,et al.  ELAM-1 mediates cell adhesion by recognition of a carbohydrate ligand, sialyl-Lex. , 1990, Science.

[46]  C. Hobel,et al.  Plasma human chorionic gonadotropin, estrone, estradiol, estriol, progesterone, and 17 alpha-hydroxyprogesterone in human pregnancy. 3. Early normal pregnancy. , 1973, American journal of obstetrics and gynecology.

[47]  Gary F. Clark,et al.  Structural Analysis of the Oligosaccharides Derived from Glycodelin, a Human Glycoprotein with Potent Immunosuppressive and Contraceptive Activities (*) , 1995, The Journal of Biological Chemistry.

[48]  A. Muchmore,et al.  Immunoregulatory properties of fractions from human pregnancy urine: evidence that human chorionic gonadotropin is not responsible. , 1977, Journal of immunology.