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The Role of Tight Junctions in Mammary Gland Function

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Abstract

Tight junctions (TJ) are cellular structures that facilitate cell-cell communication and are important in maintaining the three-dimensional structure of epithelia. It is only during the last two decades that the molecular make-up of TJ is becoming unravelled, with two major transmembrane-spanning structural protein families, called occludin and claudins, being the true constituents of the TJ. These TJ proteins are linked via specific scaffolding proteins to the cell’s cytoskeleton. In the mammary gland TJ between adjacent secretory epithelial cells are formed during lactogenesis and are instrumental in establishing and maintaining milk synthesis and secretion, whereas TJ integrity is compromised during mammary involution and also as result of mastitis and periods of mammary inflamation (including mastitis). They prevent the paracellular transport of ions and small molecules between the blood and milk compartments. Formation of intact TJ at the start of lactation is important for the establishment of the lactation. Conversely, loss of TJ integrity has been linked to reduced milk secretion and mammary function and increased paracellular transport of blood components into the milk and vice versa. In addition to acting as a paracellular barrier, the TJ is increasingly linked to playing an active role in intracellular signalling. This review focusses on the role of TJ in mammary function of the normal, non-malignant mammary gland, predominantly in ruminants, the major dairy producing species.

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Abbreviations

ECM:

Extracellular matrix

EGF:

Epidermal growth factor

IGF:

Insulin-like growth factor

LPS:

Lipopolysaccharide

LTA:

Lipoteichoic acid

MEC:

Mammary epithelial cell(s)

ODM:

Once-daily milking

TER:

Transepithelial electrical resistance

TGF:

Transforming growth factor

TJ:

Tight junction(s)

References

  1. Schneeberger EE, Lynch RD. Structure, function, and regulation of cellular tight junctions. Am J Physiol. 1992;262:L647–61.

    CAS  PubMed  Google Scholar 

  2. Stevenson BR, Keon BH. The tight junction: morphology to molecules. Annu Rev Cell Dev Biol. 1998;14:89–109.

    Article  CAS  PubMed  Google Scholar 

  3. Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S, et al. Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol. 1993;123:1777–88.

    Article  CAS  PubMed  Google Scholar 

  4. Furuse M, Fujita K, Hiiragi T, Fujimoto K, Tsukita S. Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol. 1998;141:1539–50.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Fanning AS, Jameson BJ, Jesaitis LA, Anderson JM. The tight junction protein ZO-1 establishes a link between the transmembrane protein occludin and the actin cytoskeleton. J Biol Chem. 1998;273:29745–53.

    Article  CAS  PubMed  Google Scholar 

  6. Berga SE. Electrical potentials and cell-to-cell dye movement in mouse mammary gland during lactation. Am J Physiol Cell Physiol. 1984;247:C20–5.

    CAS  Google Scholar 

  7. Stelwagen K, Davis SR, Farr VC, Prosser CG, Sherlock RA. Epithelial cell tight junction integrity and mammary blood flow during an extended milking interval in goats. J Dairy Sci. 1994;77:426–32.

    Article  CAS  PubMed  Google Scholar 

  8. Stelwagen K. Effect of milking frequency on mammary functioning and shape of the lactation curve. J Dairy Sci. 2001;84:E204–11.

    Article  CAS  Google Scholar 

  9. Brennan K, Offiah G, McSherry EA, Hopkins AM. Tight junctions: a barrier to the initiation and progression of breast cancer? J. Biomed Biotechnol. 2010;ID 460607 - doi:10.1155/2010/460607.

  10. Linzell JL, Peaker M. Changes in colostrum composition and in the permeability of the mammary epithelium at about the time of parturition in the goat. J Physiol. 1974;243:129–51.

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Pitelka DR, Hamamoto ST, Duafala JG, Nemanic K. Cell contacts in the mouse mammary gland. 1. Normal gland in postnatal development and the secretory cycle. J Cell Biol. 1973;56:797–818.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Beeman NE, Baumgartner HK, Webb PG, Schack JB, Neville MC. Disruption of occludin function in polarized epithelial cells activates the extrinsic pathway of apoptosis leading to cell extrusion without loss of transepithelial resistance. BMC Cell Biol. 2009;10:85.

    Article  PubMed Central  PubMed  Google Scholar 

  13. Beeman N, Webb PG, Baumgartner HK. Occludin is required for apoptosis when claudin-claudin interactions are disrupted. Cell Death Dis. 2012;3:e273.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Van Itallie CM, Anderson JM. The role of claudins in determining paracellular charge selectivity. Proc Am Thorac Soc. 2004;1:38–41.

    Article  PubMed  Google Scholar 

  15. Schneeberger EE. Claudins from ion-selective channels in the paracellular pathway. Focus on “Claundin extracellular domains determine paracellular charge selectively and resistance but not tight junction fibril architecture”. Am J Physiol Cell Physiol. 2003;284:1331–3.

    Article  Google Scholar 

  16. Markov AG, Kruglova NM, Fomina YA, Fromm M, Amasheh S. Altered expression of tight junction proteins in mammary epithelium after discontinued suckling in mice. Pflugers Arch - Eur J Physiol. 2012;463:391–8.

    Article  CAS  Google Scholar 

  17. Kobayashi K, Oyama S, Numata A, Rahman MM, Kumura H. Lipopolysaccharide disrupts the milk-blood barrier by modulating claudins in mammary alveolar tight junctions. PloS One. 2013;8:e62187.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Matter K, Balda MS. Signalling to and from tight junctions. Nat Rev. 2003;4:225–36.

    Article  CAS  Google Scholar 

  19. Gonzalez-Mariscal L, Bautista P, Lechuga S, Quiros M. ZO-2, a tight junction scaffold protein involved in the regulation of cell proliferation and apoptosis. Ann NY Acad Sci. 2012;1257:133–41.

    Article  CAS  PubMed  Google Scholar 

  20. Fischer A, Stuckas H, Gluth M, Russell TD, Rudolph MC, Beeman NE, et al. Impaired tight junction sealing and precocious involution in mammary glands of PKN1 transgenic mice. J Cell Sci. 2007;120:2272–83.

    Article  CAS  PubMed  Google Scholar 

  21. Akers RM. Major advances associated with hormone and growth factor regulation of mammary growth and lactation in dairy cows. J Dairy Sci. 2006;89:1222–34.

    Article  CAS  PubMed  Google Scholar 

  22. Stelwagen K, McFadden HA, Demmer J. Prolactin, alone or in combination with glucocorticoids, enhances tight junction formation and expression of the tight junction protein occludin in mammary cells. Mol Cell Endocrinol. 1999;156:55–61.

    Article  CAS  PubMed  Google Scholar 

  23. Zettl KS, Sjaastad MD, Riskin PM, Parry G, Machen TE, Firestone GL. Glucocorticoid-induced formation of tight junctions in mouse mammary epithelial cells in vitro. Proc Natl Acad Sci U S A. 1992;89:9069–73.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Singer KL, Stevenson BR, Woo PL, Firestone GL. Relationship of serine/threonine phosphorylation/dephosphorylation signaling to glucocorticoid regulation of tight junction permeability and ZO-1 distribution in nontransformed mammary epithelial cells. J Biol Chem. 1994;269:16108–15.

    CAS  PubMed  Google Scholar 

  25. Thompson GE. Cortisol and regulation of tight junctions in the mammary gland of the late-pregnant goat. J Dairy Res. 1996;63:305–8.

    Article  CAS  PubMed  Google Scholar 

  26. Stelwagen K, Van Espen DC, Verkerk GA, McFadden H, Farr VC. Elevated plasma cortisol reduces permeability of mammary tight junctions in the lactating bovine mammary epithelium. J Endocrinol. 1998;159:173–8.

    Article  CAS  PubMed  Google Scholar 

  27. Rubenstein NM, Guan Y, Woo PL, Firestone GL. Glucocorticoid down-regulation of RhoA is required for the steroid-induced organization of the junctional complex and the tight junction formation in rat mammary epithelial tumor cells. J Biol Chem. 2003;278:10353–60.

    Article  CAS  PubMed  Google Scholar 

  28. Linzell JL, Peaker M, Tayler JC. The effects of prolactin and oxytocin on milk secretion and on the permeability of the mammary epithelium in the rabbit. J Physiol. 1975;253:547–63.

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Flint DJ, Gardner M. Evidence that growth hormone stimulates milk synthesis by direct action on the mammary gland and that prolactin exerts effects on milk secretion by maintenance of mammary deoxyribonucleic acid content and tight junction status. Endocrinology. 1994;135:1119–24.

    CAS  PubMed  Google Scholar 

  30. Ollier S, Zhao X, Lacasse P. Effect of prolactin-release inhibition on milk production and mammary gland involution at drying-off in cows. J Dairy Sci. 2013;96:335–43.

    Google Scholar 

  31. Nguyen D-A, Parlow AF, Neville MC. Hormonal regulation of tight junction closure in the mouse mammary epithelium during the transition from pregnancy to lactation. J Endocrinol. 2001;170:347–56.

    Article  CAS  PubMed  Google Scholar 

  32. Gulay MS, Hayen MJ, Head HH, Bachman KC. Effect of estrogen supplemented at dry-off on temporal changes in concentrations of lactose in blood plasma of Holstein cows. J Dairy Sci. 2009;92:3815–8.

    Article  CAS  PubMed  Google Scholar 

  33. Linzell JL, Peaker M. The effects of oxytocin and milk removal on milk secretion in the goat. J Physiol. 1971;216:717–34.

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Allen JC. Milk synthesis and secretion rates in cows with milk composition changed by oxytocin. J Dairy Sci. 1990;73:975–84.

    Article  CAS  PubMed  Google Scholar 

  35. Woo PL, Vha HH, Singer KL, Firestone GL. Antagonistic regulation of tight junction dynamics by glucocorticoids and transforming growth factor-β in mouse mammary epithelial cells. J Biol Chem. 1996;271:404–12.

    Article  CAS  PubMed  Google Scholar 

  36. Paye JM, Akers RMHWR, Forsten-Williams K. Autocrine production of insulin-like growth factor-I (IGF-I) affects paracellular transport across epithelial cells in vitro. Cell Commun Adhes. 2007;14:85–98.

    Article  CAS  PubMed  Google Scholar 

  37. Pitelka DR, Taggart BN, Hamamoto ST. Effects of extracellular calcium depletion on membrane topography and occluding junctions of mammary epithelium cells in culture. J Cell Biol. 1983;96:613–24.

    Article  CAS  PubMed  Google Scholar 

  38. Philbrick WM, Wysolmerski JJ, Galbraith S, Holt E, Orloff JJ, Yang KH, et al. Defining the roles of parathyroid hormone-related protein in normal physiology. Physiol R. 1996;76:127–73.

    CAS  Google Scholar 

  39. Stelwagen K, Callaghan MR. Regulation of mammary tight junctions through parathyroid hormone-related peptide-induced activation of apical calcium channels. J Endocrinol. 2003;178:257–64.

    Article  CAS  PubMed  Google Scholar 

  40. Thompson GE, Ratcliffe WA, Hughes S, Abbas SK, Care AD. Local control of parathyroid hormone-related protein secretion by the mammary gland of the goat. Comp Biochem Physiol. 1994;108A:485–90.

    Article  CAS  Google Scholar 

  41. Collier RJ, Hernandez LL, Horseman ND. Serotonin as a homeostatic regulator of lactation. Dom Anim Endocrinol. 2012;43:161–70.

    Article  CAS  Google Scholar 

  42. Stull MA, Pai V, Vomachka AJ, Marshall AM, Jacob GE, Horseman ND. Mammary gland homeostasis employs serotonergic regulation of epithelial tight junctions. PNAS. 2007;104:16708–13.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Hernandez LL, Collier JL, Vomachka AJ, Collier RJ, Horseman ND. Suppression of lactation and acceleration of involution in the bovine mammary gland by a selective serotonin reuptake inhibitor. J Endocrinol. 2011;209:45–54.

    Article  CAS  PubMed  Google Scholar 

  44. Kobayashi K, Kumura H. Distinct behaviour of claudin-3 and -4 around lactation period in mammary alveolus in mice. Histochem Cell Biol. 2011;136:587–94.

    Article  CAS  PubMed  Google Scholar 

  45. Fleet IR, Goode JA, Hamon MH, Laurie MS, Linzell JL, Peaker M. Secretory activity of goat mammary glands during pregnancy and the onset of lactation. J Physiol. 1975;251:763–73.

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Morgan G, Wooding FB. A freeze-fracture study of tight junction structure in sheep mammary gland epithelium during pregnancy and lactation. J Dairy Res. 1982;49:1–11.

    Article  CAS  PubMed  Google Scholar 

  47. Neville MC, Peaker M. Ionized calcium in milk and the integrity of the mammary epithelium in the goat. J Physiol. 1981;313:561–70.

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Butler JE. Synthesis and distribution of immunoglobulins. J Am Vet Med Assoc. 1973;163:795–8.

    CAS  Google Scholar 

  49. Smolenski G, Haines S, Kwan FY, Bond J, Farr VDSR, Stelwagen K, et al. Characterisation of host defence proteins in milk using a proteomics approach. J Proteome Res. 2007;6:207–15.

    Article  CAS  PubMed  Google Scholar 

  50. Wheeler TT, Hodgkinson AJ, Prosser CG, Davis SR. Immune components of colostrum and milk - a historical perspective. J Mammary Gland Biol Neoplasia. 2007;12:237–47.

    Article  PubMed  Google Scholar 

  51. Stelwagen K, Carpenter E, Haigh B, Hodgkinson A, Wheeler T. Immune components of bovine milk and colostrum. J Anim Sci. 2009;87 Suppl 1:3–9.

    CAS  PubMed  Google Scholar 

  52. Bush LJ, Staley TE. Absoption of colostral immunuglobulins in new born calves. J Dairy Sci. 1980;63:672–80.

    Article  CAS  PubMed  Google Scholar 

  53. Guy MA, McFadden TB, Cockrell DCBTE. Effects of unilateral prepartum milking on concentrations of immunoglobulin G1 and prolactin in colostrum. J Dairy Sci. 1994;77:3584–91.

    Article  CAS  PubMed  Google Scholar 

  54. Stelwagen K, Farr VC, Davis SR, Prosser CG. EGTA-induced disruption of epithelial cell tight junctions in the lactating caprine mammary gland. Am J Physiol. 1995;269:R848–55.

    CAS  PubMed  Google Scholar 

  55. Stelwagen K, Farr VC, McFadden HA, Prosser CG, Davis SR. Time course of milk accumulation-induced opening of mammary tight junctions and blood clearance of milk components. Am J Physiol. 1997;273:R379–86.

    CAS  PubMed  Google Scholar 

  56. Peaker M. The effect of raised intramammary pressure on mammary function in the goat in relation to the cessation of lactation. J Physiol. 1980;301:415–28.

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Singh K, Dobson J, Phyn CVC, Davis SR, Farr VC, Molenaar AJ, et al. Milk accumulation decreases expression of genes involved in cell-extracellular matrix communication and is associated with induction of apoptosis in the bovine mammary gland. Livest Prod Sci. 2005;98:67–78.

    Article  Google Scholar 

  58. Stelwagen K, Knight CH, Farr VC, Davis SR, Prosser CG, McFadden TB. Continuous versus single drainage of milk from the bovine mammary gland during a 24-hour period. Exp Physiol. 1996;81:141–9.

    CAS  PubMed  Google Scholar 

  59. Stelwagen K, Phyn CVC, Davis SR, Guinard-Flament J, Pomiés D, Roche JR, et al. Invited review: reduced milking frequency: milk production and management. J Dairy Sci. 2013;96:3401–13.

    Article  CAS  PubMed  Google Scholar 

  60. Erdman RA, Varner M. Fixed yield responses to increased milking frequency. J Dairy Sci. 1995;78:1199–203.

    Article  CAS  PubMed  Google Scholar 

  61. Sorensen BA, Muir DD, Knight CH. Thrice-daily milking throughout lactation maintains epithelial integrity and thereby improves milk protein quality. J Dairy Res. 2001;68:15–25.

    Article  CAS  PubMed  Google Scholar 

  62. Fleet IR, Peaker M. Mammary function and its control at the cessation of lactation in the goat. J Physiol Lond. 1978;279:491–507.

    CAS  PubMed Central  PubMed  Google Scholar 

  63. McMahon CD, Farr VC, Singh K, Wheeler TT, Davis SR. Decreased expression of ß1-integrin and focal adhesion kinase in epithelial cells may initiate involution of mammary glands. J Cell Physiol. 2004;200:318–25.

    Article  CAS  PubMed  Google Scholar 

  64. Phyn CVC. Regulation of tight junction proteins during engorgement of the mammary gland. 1996. PhD Thesis. Massey University, Palmerston North, New Zealand.

  65. Stelwagen K, Ormrod DJ. An anti-inflammatory component derived from milk of hyper-immunised cows reduces tight junction permeability in vitro. Inflam Res. 1998;47:384–8.

    Article  CAS  Google Scholar 

  66. Shamay A, Shapiro F, Mabjeesh SJ, Silanikove N. Casein-derived phosphopeptides disrupt tight junction integrity, and precipitously dry up milk secretion in goats. Life Sci. 2002;70:2707–19.

    Article  CAS  PubMed  Google Scholar 

  67. Shamay A, Shapiro F, Leitner G, Silanikove N. Infusions of casein hydrolyzates into the mammary gland disrupt tight junction integrity and induce involution in cows. J Dairy Sci. 2003;86:1250–8.

    Article  CAS  PubMed  Google Scholar 

  68. Playford RJ, MacDonald CE, Calnan DP, Floyd DN, Podas T, Johnson W, et al. Co-administration of the health food supplement, bovine colostrum, reduces the acute non-steroidal anti-inflammatory drug-induced increase in intestinal permeability. Clin Sci (Lond). 2001;100:627–33.

    Article  CAS  Google Scholar 

  69. Prosser CG, Stelwagen K, Cummins R, Guerin P, Gill N, Milne C. Reduction in heat-induced gastrointestinal hyperpermeability in rats by bovine colostrum and goat milk powders. J Appl Physiol. 2004;96:650–4.

    Article  CAS  PubMed  Google Scholar 

  70. Buckley JD, Buler RN, Southcott E, Brinkworth GD. Bovine colostrum supplementation during running training increases intestinal permeability. Nutrients. 2009;1:224–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Kotler BM, Kerstetter JE, Ansogna KL. Claudins, dietary milk proteins, and intestinal barrier regulation. Nutr Rev. 2013;71:60–5.

    Article  PubMed  Google Scholar 

  72. Bodammer P, Kerkhoff C, Maletzki C, Lamprecht G. Bovine colostrum increases pore-forming claudin-2 protein expression but paradoxically not ion permeability possibly by a change of the intestinal cytokine milieu. PloS One. 2013;8:e64210.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Lin Y, Xia L, Turner JD, Zhao X. Morphologic observation of neutrophil diapedesis across bovine mammary gland epithelium in vitro. Am J Vet Res. 1995;56:203–7.

    CAS  PubMed  Google Scholar 

  74. Warshakoon HJ, Burns MR, David SA. Structure-activity relationships of antimicrobial and lipoteichoic acid-sequestering properties in polyamine sulfonamides. Antimicrob Agents Chemother. 2009;53:57–62.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Lehmann M, Wellnitz O, Bruckmaier RM. Concomitant lipopolysaccharide-induced transfer of blood-derived components including immunoglobulins into milk. J Dairy Sci. 2013;96:889–96.

    Article  CAS  PubMed  Google Scholar 

  76. Wellnitz O, Arnold ET, Lehmann M, Bruckmaier RM. Differential immunoglobulin transfer during mastitis challenge by pathogen-specific components. J Dairy Sci. 2013;96:1681–4.

    Article  CAS  PubMed  Google Scholar 

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Stelwagen, K., Singh, K. The Role of Tight Junctions in Mammary Gland Function. J Mammary Gland Biol Neoplasia 19, 131–138 (2014). https://doi.org/10.1007/s10911-013-9309-1

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