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KALLIKREINS AND KININS IN INFLAMMATORY-LIKE EVENTS IN THE REPRODUCTIVE TRACT
Pharmacological Research, Vol. 35, No. 6, 1997
KALLIKREINS AND KININS IN INFLAMMATORY-LIKE EVENTS IN THE REPRODUCTIVE TRACT JUDITH CLEMENTS, ANNIE MUKHTAR, SHEN YAN and ANDREW HOLLAND Centre for Molecular Biotechnology, Queensland Uni¨ersity of Technology, Brisbane and Prince Henry’s Institute of Medical Research, Melbourne, Australia Accepted 13 May 1997
The normal reproductive events of proliferation of the endometrial lining of the uterus during the menstrual cycle and ovulation have been likened to inflammatory-like events. The kallikrein-kinin system is involved in inflammatory processes in many tissues. In this review, we identify which components of the kallikrein-kinin system } the enzyme, tissue kallikrein; the substrate, low molecular weight kininogen and the effector receptor for the generated bradykinin peptide, the B2 receptor } have been identified in the uterus and ovary and their known involvement in the function of these organs. All three components have been localized to the glandular epithelial cells of the human endometrium. Tissue kallikrein gene expression is elevated midcycle when estrogens levels are also rising. This is also a time of extensive endometrial proliferation and tissue remodelling in preparation for embryo implantation, an event which is likened to other inflammatory processes. Similarly, tissue kallikrein gene expression was elevated following the estrogen surge at proestrous in the rat uterus, suggesting tissue kallikrein gene expression may be regulated by estrogens. Tissue kallikrein enzyme activity and gene expression has been demonstrated in the rat ovary and shown to be variously altered at the time of ovulation. Bradykinin has also been implicated in the expulsion of the ovum at the time of ovulation. These findings show that various components of the kallikrein-kinin system are present in the uterus and ovary. Further studies are required to more fully delineate their role in reproductive function. Q 1997 The Italian Pharmacological Society KEY
WORDS:
tissue kallikreins, kinins, inflammation, uterus, ovary.
The kallikrein]kinin system is involved in the process of inflammation at sites of trauma and damage in many tissues w1, 2x. The inflammatory response is characterised by vasodilation, vascular permeability, oedema and pain. Mast cell activation and neutrophil invasion of the site is also typical as is the involvement of cytokines, prostaglandins and various growth factors with the kallikrein]kinin system w1, 2x. The cyclic regeneration of the endometrial lining of the uterus during the proliferative preparation for implantation has been likened to an inflammatory response. Generally, this event involves the proliferation of the endometrial lining, angiogenesis, increased blood flow, vascular permeability, infiltration of neutrophils, mast cell activation and remodelling of the uterine lining following menstruation w3x. Similarly, the hyperaemic expansion of the ovarian follicle prior to ovulation has also been suggested to be an inflammatory-like event involving similar biological processes as in the uterus w4x. Prostaglandins, cytokines and growth factors are also key players in these reproductive events w3, 4x. Tissue kallikrein is a member of a multigene family Ž KLK . of highly conserved serine proteases. 1043]6618r97r060537]04r$25.00r0rfr970183
The rat KLKgene family consists of 13 genes; the human family, however, is much smaller and consists of just three genes w5, 6x. We have previously extensively characterised the expression and hormonal regulation of the tissue kallikrein Ž rKLK . gene family in the rat w7]14x. We have detailed the expression of various rKLK genes, including rKLK1 or tissue kallikrein, in the salivary gland, kidney, pituitary, gastro-intestinal tract and prostate, testis and ovary of the reproductive tract w7]11x. These genes are expressed in a tissue-specific manner, that is not all members of the family are expressed in all tissues. For instance rKLK1 is almost ubiquitously expressed, but rKLK2 or tonin is only expressed in the salivary glands. These genes are also variously regulated by the steroid hormones androgen and estrogen and thyroid hormone. The expression of all the rKLK genes, except for rKLK1, is regulated by androgen and thyroid hormone in the salivary gland w12, 13x. Similarly rKLK8 and rKLK9 expression is androgen-dependent in the prostate w13x. rKLK1 expression in the rat pituitary, however, is estrogen dependent w14x. In the studies oulined here, we have further deQ1997 The Italian Pharmacological Society
538
termined which KLK genes are expressed in the rat female reproductive tract and extended these studies to the human. We have also characterised the steroid hormonal regulation, by estrogen and progesterone, of the expression of these genes. We have further explored the possibility that the tissue kallikrein] kinin system may be involved in inflammatory-like responses in the normal function of the female reproductive tract and examined the localisation and action of other components of the tissue kallikrein]kinin system, LMW kininogen and the B 2 bradykinin receptor, in these tissues. In previous studies, other investigators had detected tissue kallikrein activity in tissue extracts of rat and human uterus w15, 16x. The kallikrein]kinin system has previously been implicated in the processes of implantation and parturition w16, reviewed in 2, 6x. Kallikrein andror bradykinin can stimulate prostaglandin production in human decidual chorion cells in culture w17x. The bradykinin B 2 receptor is expressed in the rat and human uterus and is present on human decidual cells w17x. LMW kininogen has also been localised to the glandular epithelial cells of the human endometrium and arterioles of the myometrium w18x. Thus it seems probable that a local tissue kallikrein]kinin system is present and active in the uterus of the rat and human. Expression of the KLK1 gene, which encodes tissue kallikrein, had not yet been confirmed in these tissues. We have shown that the three human KLK genes, including KLK1 or tissue kallikrein, are expressed in the endometrial lining of the human uterus w19x. Similarly, several rKLK genes, including rKLK1 are expressed in the rat uterus ŽShen and Clements, manuscript in preparation.. To determine if the expression of these genes is cyclically regulated by the female sex steroid hormones, estrogen andror progesterone, we have examined the expression of KLK1 or tissue kallikrein in the human endometrium across the menstrual cycle and the rat uterus during the estrus cycle. We have shown that KLK1 expression in the human endometrium is elevated midcycle at the time of elevated estrogen levels and extensive endometrial proliferation in preparation for implantation w20x. The levels of KLK1 expression then fall in the later part of the secretory phase of the menstrual cycle, at a time of rising progesterone levels, suggesting that KLK1 expression may be negatively regulated by progesterone. Tissue kallikrein, its substrate LMW kininogen and the bradykinin B 2 receptor are co-localised in the glandular and luminal epithelial cells of the human endometrium, providing further evidence for a local kallikrein]kinin system w18, 20, Clements and Murone, unpublished observations.. In the rat uterus, rKLK1 gene expression was similarly elevated following the peak of increased circulating estrogen levels at pro-estrous during the estrous
Pharmacological Research, Vol. 35, No. 6, 1997
cycle. In contrast to the human, tissue kallikrein appears to be localised to the stroma and not the glandular or luminal epithelium of the rat endometrium ŽShen and Clements, manuscript in preparation.. These findings confirm the presence of a locally active kallikrein]kinin system in the human and rat uterus. The endometrial or uterine Žrat. expression of rKLK1 or tissue kallikrein appears to be regulated by estrogen in both species. This is in keeping with previous findings which suggested tissue kallikrein activity was affected by high estrogen levels during the estrous cycle in the rat uterus w16x. Similarly, it is in keeping with the previous observation of estrogen regulation of rKLK1 expression in the rat pituitary w14x. Progesterone regulation of tissue kallikrein expression or activity has not been reported previously. Of interest is the apparent difference in cellular localisation of tissue kallikrein and the bradykinin receptor in the rat and human endometrium. In the human, all components of the tissue kallikrein]kinin system are localised to the glandular and luminal epithelial cells wheras in the rat, the localisation of tissue kallikrein and the B 2 receptor, at least appear to be stromal rather than epithelial Žsee above.. Further studies will be necesssary to determine the reasons for these species differences in the cell-specific localisation of the kallikrein]kinin system. The precise role of the kallikrein]kinin system in the cyclical inflammatory-like events preceeding implantation in the endometrial lining of the uterus also is yet to be established. Tissue kallikrein activity has been previously detected in the rat ovary w21, 22x. This enzyme activity has been shown by two different groups to be variously elevated or decreased at the time of ovulation in a gonadotrophin-stimulated immature rat model of ovulation w21, 22x. Ovulation and the rise in kallikrein enzyme activity, in these animals could be blocked by indomethacin and the progesterone antagonist, epostane w23x. This finding suggested that not only was tissue kallikrein important to the ovulatory process but that this enzyme was interacting with progesterone and prostaglandins in this response. In addition, bradykinin has been implicated in the contractile expulsion of the ovum at ovulation and is able to induce ovulation when perfused through the isolated rat ovary w24x. This latter effect was blocked by the addition of a bradykinin antagonist. Thus the tissue kallikrein]kinin system would appear to be important in the ovulatory process. What was not clear from the studies of Espey w21x and Gao w22x was which profile of tissue kallikrein activity clearly reflected true tissue kallikrein activity. These authors used different chromogenic substrates for their assays which to different degrees, can variously detect other kallikrein-like enzymes; the
Pharmacological Research, Vol. 35, No. 6, 1997
substrate used by Gao being more specific for tissue kallikrein. We have previously shown that several rKLK genes, including rKLK1 or tissue kallikrein, are expressed in the rat ovary Ž11.. The majority of these genes are expressed in the granulosa cell, although the cell-type to which rKLK1 is localised is unknown. In the current study, using the same gonadotrophin-stimulated immature rat model of ovulation w21]23x, we sought to determine which expression profile for the individual rKLK genes would best reflect the above enzymic patterns. In this model, several different patterns of expression were observed for the individual rKLK genes. rKLK1rtissue kallikrein expression was elevated following gonadotrophin stimulation but low at the time of ovulation and best reflects the enzymic pattern observed by Gao et al. w22x. These findings add weight to the view that some of the earlier enzymatic studies may have measured other kallikrein-like activities in addition to tissue kallikrein. These observations also highlight the need for specific substrates or multisubtrate profiles to discriminate between the multiple enzymes in the tissue kallikrein gene family. Further studies are needed to more precisely determine the role of the kallikrein]kinin system and other enzymes of the rKLK family in ovulation and other aspects of ovarian function. These studies support the view that the kallikrein]kinin system is involved in inflammatory-like responses which are a crucial part of the normal function of the ovary and uterus. The specific role of the kallikrein]kinin system in these reproductive events is still not clearly understood but merits further investigation.
ACKNOWLEDGEMENTS This paper was presented on the occasion of the Satellite Meeting of the Gordon Conference on Kallikreins and Kinins, entitled ‘The kallikrein]kinin System: Pharmacology, Organ Protection and Gene Therapy’ organized by Paolo Madeddu and held at the University of Sassari, Italy, on May 3, 1997.
REFERENCES 1. Hall JM, Morton IKM. The pharmacology and immunopharmacology of kinin receptors. In: Farmer SG. ed. The kinin system. London: Academic Press, 1997; pp. 9]44. 2. Bhoola KD, Figueroa CD, Worthy K. Bioregulation of kinins: kallikreins, kininogens and kinases. Pharmacol Re¨ 1992; 44: 1]80. 3. Tabibzadeh S. Human endometrium: an active site of cytokine production and action. Endocr Re¨ 1991; 12: 272]90.
539
4. Espey LL. Ovulation as an inflammatory reaction } a hypothesis. Biol Reprod 1980; 22: 73]106. 5. Clements JA. The glandular kallikrein family of enzymes: tissue-specific expression and hormonal regulation. Endocr Re¨ 1989; 10: 393]419. 6. Clements JA. The human kallikrein gene family: a diversity of expression and function. Mol Cell Endocrinol 1994; 99: C1]6. 7. Fuller PJ, Clements JA, Whitfeld PL, Funder JW. Kallikrein gene expression in the rat anterior pituitary. Mol Cell Endocrinol 1985; 39: 99]105. 8. Fuller PJ, Verity K, MacDonald RJ, Matheson BM, Clements JA. Kallikrein gene expression in the rat gastrointestinal tract. Biochem J 1989; 264: 133]6. 9. Clements JA, Matheson BA, Funder JW. Tissuespecific developmental expression of the kallikrein gene family in the rat. J Biol Chem 265: 1077]81. 10. Clements JA, Mukhtar A, Ehrlich A, Fuller P. A re-evaluation of the tissue-specific pattern of expression of the rat kallikrein gene family. In: Fritz H, Muller-Esterl W, Jochum M, Roscher A, Luppertz K. eds. Recent Progress on Kinins. Agents and Actions. Basel: Birkhauser Verlag, 1992; 38rI: pp. 34]41. 11. Clements JA, Mukhtar A, Holland AM, Ehrlich A, Fuller PJ. Kallikrein gene family expression in the rat ovary: localization to the granulosa cell. Endocrinology 1995; 136: 1137]44. 12. Clements JA, Matheson BA, Funder JW. Tissuespecific regulation of the expression of rat kallikrein gene family members by thyroid hormone. Biochem J 1990; 3: 745]50. 13. Clements JA, Matheson BA, Wines DR, Brady JM, MacDonald RJ, Funder JW. Androgen dependence of specific kallikrein gene family members expressed in rat prostate. J Biol Chem 263: 16132]7. 14. Clements JA, Fuller PJ, McNally M, Nikolaidis I, Funder JW. Estrogen regulation of kallikrein gene expression in the rat anterior pituitary. Endocrinology 1986; 119: 268]73. 15. Malofiejew M. Kallikrein-like activity in human myometrium, placenta and amniotic fluid. Biochem Pharmacol 1973; 222: 123]7. 16. Valdes G, Corthorn J, Scicli AG, Gaete V, Soto J, Ortiz ME, Foradori A, Saed GM. Uterine kallikrein in the early pregnant rat. Biol Reprod 1993; 49: 802]8. 17. Rehbock J, Chondromatidou A, Buchinger P, Hermann A. The B 2 receptor on cultured human decidua cells: release of arachidonic acid by bradykinin. Immunopharmacology 1996; 33: 164]6. 18. Figueroa CD, Gonzalez CD, Muller-Esterl W, Bhoola KD. Cellular localization of human kininogens. In: Bonner G, Fritz H, Scholkens B, Dietze G. eds. Recent Progress in Kinins. Basel: Birkenhauser Verlag, 1992; 38rI: pp. 617]26. 19. Clements JA, Mukhtar A. Glandular kallikreins and prostate-specific antigen are expressed in the human endometrium. J Clin Endoc Metab 1994; 78: 1536]9. 20. Clements JA, Mukhtar A, Ehrlich A, Yap B. Glandular kallikrein gene expression in the human uterus. Braz J Med Biol Res 1994; 27: 1855]63. 21. Espey LL, Tanaka N, Winn V, Okamura H. Increase in ovarian kallikrein activity during ovulation in the gonadotrophin-primed immature rat. J Reprod Fert 1989; 87: 503]8. 22. Gao X, Greenbaum LM, Mahesh VB, Brann DW. Characterization of the kinin system in the ovary during ovulation in the rat. Biol Reprod 47: 945]51.
540
23. Tanaka N, Espey LL, Stacy S, Okamura H. Epostane and indomethacin actions on ovarian kallikrein and plasminogen activator activities during ovulation in the gonadotropin-primed immature rat. Biol Reprod 1992; 46: 665]70.
Pharmacological Research, Vol. 35, No. 6, 1997
24. Hellberg P, Larson L, Olofsson J, Hedin L, Brannstrom M. Stimulatory effects on the ovulatory process in the in vitro-perfused rat ovary. Biol Reprod 1991; 44: 269]74.
KALLIKREINS AND KININS IN INFLAMMATORY-LIKE EVENTS IN THE REPRODUCTIVE TRACT JUDITH CLEMENTS, ANNIE MUKHTAR, SHEN YAN and ANDREW HOLLAND Centre for Molecular Biotechnology, Queensland Uni¨ersity of Technology, Brisbane and Prince Henry’s Institute of Medical Research, Melbourne, Australia Accepted 13 May 1997
The normal reproductive events of proliferation of the endometrial lining of the uterus during the menstrual cycle and ovulation have been likened to inflammatory-like events. The kallikrein-kinin system is involved in inflammatory processes in many tissues. In this review, we identify which components of the kallikrein-kinin system } the enzyme, tissue kallikrein; the substrate, low molecular weight kininogen and the effector receptor for the generated bradykinin peptide, the B2 receptor } have been identified in the uterus and ovary and their known involvement in the function of these organs. All three components have been localized to the glandular epithelial cells of the human endometrium. Tissue kallikrein gene expression is elevated midcycle when estrogens levels are also rising. This is also a time of extensive endometrial proliferation and tissue remodelling in preparation for embryo implantation, an event which is likened to other inflammatory processes. Similarly, tissue kallikrein gene expression was elevated following the estrogen surge at proestrous in the rat uterus, suggesting tissue kallikrein gene expression may be regulated by estrogens. Tissue kallikrein enzyme activity and gene expression has been demonstrated in the rat ovary and shown to be variously altered at the time of ovulation. Bradykinin has also been implicated in the expulsion of the ovum at the time of ovulation. These findings show that various components of the kallikrein-kinin system are present in the uterus and ovary. Further studies are required to more fully delineate their role in reproductive function. Q 1997 The Italian Pharmacological Society KEY
WORDS:
tissue kallikreins, kinins, inflammation, uterus, ovary.
The kallikrein]kinin system is involved in the process of inflammation at sites of trauma and damage in many tissues w1, 2x. The inflammatory response is characterised by vasodilation, vascular permeability, oedema and pain. Mast cell activation and neutrophil invasion of the site is also typical as is the involvement of cytokines, prostaglandins and various growth factors with the kallikrein]kinin system w1, 2x. The cyclic regeneration of the endometrial lining of the uterus during the proliferative preparation for implantation has been likened to an inflammatory response. Generally, this event involves the proliferation of the endometrial lining, angiogenesis, increased blood flow, vascular permeability, infiltration of neutrophils, mast cell activation and remodelling of the uterine lining following menstruation w3x. Similarly, the hyperaemic expansion of the ovarian follicle prior to ovulation has also been suggested to be an inflammatory-like event involving similar biological processes as in the uterus w4x. Prostaglandins, cytokines and growth factors are also key players in these reproductive events w3, 4x. Tissue kallikrein is a member of a multigene family Ž KLK . of highly conserved serine proteases. 1043]6618r97r060537]04r$25.00r0rfr970183
The rat KLKgene family consists of 13 genes; the human family, however, is much smaller and consists of just three genes w5, 6x. We have previously extensively characterised the expression and hormonal regulation of the tissue kallikrein Ž rKLK . gene family in the rat w7]14x. We have detailed the expression of various rKLK genes, including rKLK1 or tissue kallikrein, in the salivary gland, kidney, pituitary, gastro-intestinal tract and prostate, testis and ovary of the reproductive tract w7]11x. These genes are expressed in a tissue-specific manner, that is not all members of the family are expressed in all tissues. For instance rKLK1 is almost ubiquitously expressed, but rKLK2 or tonin is only expressed in the salivary glands. These genes are also variously regulated by the steroid hormones androgen and estrogen and thyroid hormone. The expression of all the rKLK genes, except for rKLK1, is regulated by androgen and thyroid hormone in the salivary gland w12, 13x. Similarly rKLK8 and rKLK9 expression is androgen-dependent in the prostate w13x. rKLK1 expression in the rat pituitary, however, is estrogen dependent w14x. In the studies oulined here, we have further deQ1997 The Italian Pharmacological Society
538
termined which KLK genes are expressed in the rat female reproductive tract and extended these studies to the human. We have also characterised the steroid hormonal regulation, by estrogen and progesterone, of the expression of these genes. We have further explored the possibility that the tissue kallikrein] kinin system may be involved in inflammatory-like responses in the normal function of the female reproductive tract and examined the localisation and action of other components of the tissue kallikrein]kinin system, LMW kininogen and the B 2 bradykinin receptor, in these tissues. In previous studies, other investigators had detected tissue kallikrein activity in tissue extracts of rat and human uterus w15, 16x. The kallikrein]kinin system has previously been implicated in the processes of implantation and parturition w16, reviewed in 2, 6x. Kallikrein andror bradykinin can stimulate prostaglandin production in human decidual chorion cells in culture w17x. The bradykinin B 2 receptor is expressed in the rat and human uterus and is present on human decidual cells w17x. LMW kininogen has also been localised to the glandular epithelial cells of the human endometrium and arterioles of the myometrium w18x. Thus it seems probable that a local tissue kallikrein]kinin system is present and active in the uterus of the rat and human. Expression of the KLK1 gene, which encodes tissue kallikrein, had not yet been confirmed in these tissues. We have shown that the three human KLK genes, including KLK1 or tissue kallikrein, are expressed in the endometrial lining of the human uterus w19x. Similarly, several rKLK genes, including rKLK1 are expressed in the rat uterus ŽShen and Clements, manuscript in preparation.. To determine if the expression of these genes is cyclically regulated by the female sex steroid hormones, estrogen andror progesterone, we have examined the expression of KLK1 or tissue kallikrein in the human endometrium across the menstrual cycle and the rat uterus during the estrus cycle. We have shown that KLK1 expression in the human endometrium is elevated midcycle at the time of elevated estrogen levels and extensive endometrial proliferation in preparation for implantation w20x. The levels of KLK1 expression then fall in the later part of the secretory phase of the menstrual cycle, at a time of rising progesterone levels, suggesting that KLK1 expression may be negatively regulated by progesterone. Tissue kallikrein, its substrate LMW kininogen and the bradykinin B 2 receptor are co-localised in the glandular and luminal epithelial cells of the human endometrium, providing further evidence for a local kallikrein]kinin system w18, 20, Clements and Murone, unpublished observations.. In the rat uterus, rKLK1 gene expression was similarly elevated following the peak of increased circulating estrogen levels at pro-estrous during the estrous
Pharmacological Research, Vol. 35, No. 6, 1997
cycle. In contrast to the human, tissue kallikrein appears to be localised to the stroma and not the glandular or luminal epithelium of the rat endometrium ŽShen and Clements, manuscript in preparation.. These findings confirm the presence of a locally active kallikrein]kinin system in the human and rat uterus. The endometrial or uterine Žrat. expression of rKLK1 or tissue kallikrein appears to be regulated by estrogen in both species. This is in keeping with previous findings which suggested tissue kallikrein activity was affected by high estrogen levels during the estrous cycle in the rat uterus w16x. Similarly, it is in keeping with the previous observation of estrogen regulation of rKLK1 expression in the rat pituitary w14x. Progesterone regulation of tissue kallikrein expression or activity has not been reported previously. Of interest is the apparent difference in cellular localisation of tissue kallikrein and the bradykinin receptor in the rat and human endometrium. In the human, all components of the tissue kallikrein]kinin system are localised to the glandular and luminal epithelial cells wheras in the rat, the localisation of tissue kallikrein and the B 2 receptor, at least appear to be stromal rather than epithelial Žsee above.. Further studies will be necesssary to determine the reasons for these species differences in the cell-specific localisation of the kallikrein]kinin system. The precise role of the kallikrein]kinin system in the cyclical inflammatory-like events preceeding implantation in the endometrial lining of the uterus also is yet to be established. Tissue kallikrein activity has been previously detected in the rat ovary w21, 22x. This enzyme activity has been shown by two different groups to be variously elevated or decreased at the time of ovulation in a gonadotrophin-stimulated immature rat model of ovulation w21, 22x. Ovulation and the rise in kallikrein enzyme activity, in these animals could be blocked by indomethacin and the progesterone antagonist, epostane w23x. This finding suggested that not only was tissue kallikrein important to the ovulatory process but that this enzyme was interacting with progesterone and prostaglandins in this response. In addition, bradykinin has been implicated in the contractile expulsion of the ovum at ovulation and is able to induce ovulation when perfused through the isolated rat ovary w24x. This latter effect was blocked by the addition of a bradykinin antagonist. Thus the tissue kallikrein]kinin system would appear to be important in the ovulatory process. What was not clear from the studies of Espey w21x and Gao w22x was which profile of tissue kallikrein activity clearly reflected true tissue kallikrein activity. These authors used different chromogenic substrates for their assays which to different degrees, can variously detect other kallikrein-like enzymes; the
Pharmacological Research, Vol. 35, No. 6, 1997
substrate used by Gao being more specific for tissue kallikrein. We have previously shown that several rKLK genes, including rKLK1 or tissue kallikrein, are expressed in the rat ovary Ž11.. The majority of these genes are expressed in the granulosa cell, although the cell-type to which rKLK1 is localised is unknown. In the current study, using the same gonadotrophin-stimulated immature rat model of ovulation w21]23x, we sought to determine which expression profile for the individual rKLK genes would best reflect the above enzymic patterns. In this model, several different patterns of expression were observed for the individual rKLK genes. rKLK1rtissue kallikrein expression was elevated following gonadotrophin stimulation but low at the time of ovulation and best reflects the enzymic pattern observed by Gao et al. w22x. These findings add weight to the view that some of the earlier enzymatic studies may have measured other kallikrein-like activities in addition to tissue kallikrein. These observations also highlight the need for specific substrates or multisubtrate profiles to discriminate between the multiple enzymes in the tissue kallikrein gene family. Further studies are needed to more precisely determine the role of the kallikrein]kinin system and other enzymes of the rKLK family in ovulation and other aspects of ovarian function. These studies support the view that the kallikrein]kinin system is involved in inflammatory-like responses which are a crucial part of the normal function of the ovary and uterus. The specific role of the kallikrein]kinin system in these reproductive events is still not clearly understood but merits further investigation.
ACKNOWLEDGEMENTS This paper was presented on the occasion of the Satellite Meeting of the Gordon Conference on Kallikreins and Kinins, entitled ‘The kallikrein]kinin System: Pharmacology, Organ Protection and Gene Therapy’ organized by Paolo Madeddu and held at the University of Sassari, Italy, on May 3, 1997.
REFERENCES 1. Hall JM, Morton IKM. The pharmacology and immunopharmacology of kinin receptors. In: Farmer SG. ed. The kinin system. London: Academic Press, 1997; pp. 9]44. 2. Bhoola KD, Figueroa CD, Worthy K. Bioregulation of kinins: kallikreins, kininogens and kinases. Pharmacol Re¨ 1992; 44: 1]80. 3. Tabibzadeh S. Human endometrium: an active site of cytokine production and action. Endocr Re¨ 1991; 12: 272]90.
539
4. Espey LL. Ovulation as an inflammatory reaction } a hypothesis. Biol Reprod 1980; 22: 73]106. 5. Clements JA. The glandular kallikrein family of enzymes: tissue-specific expression and hormonal regulation. Endocr Re¨ 1989; 10: 393]419. 6. Clements JA. The human kallikrein gene family: a diversity of expression and function. Mol Cell Endocrinol 1994; 99: C1]6. 7. Fuller PJ, Clements JA, Whitfeld PL, Funder JW. Kallikrein gene expression in the rat anterior pituitary. Mol Cell Endocrinol 1985; 39: 99]105. 8. Fuller PJ, Verity K, MacDonald RJ, Matheson BM, Clements JA. Kallikrein gene expression in the rat gastrointestinal tract. Biochem J 1989; 264: 133]6. 9. Clements JA, Matheson BA, Funder JW. Tissuespecific developmental expression of the kallikrein gene family in the rat. J Biol Chem 265: 1077]81. 10. Clements JA, Mukhtar A, Ehrlich A, Fuller P. A re-evaluation of the tissue-specific pattern of expression of the rat kallikrein gene family. In: Fritz H, Muller-Esterl W, Jochum M, Roscher A, Luppertz K. eds. Recent Progress on Kinins. Agents and Actions. Basel: Birkhauser Verlag, 1992; 38rI: pp. 34]41. 11. Clements JA, Mukhtar A, Holland AM, Ehrlich A, Fuller PJ. Kallikrein gene family expression in the rat ovary: localization to the granulosa cell. Endocrinology 1995; 136: 1137]44. 12. Clements JA, Matheson BA, Funder JW. Tissuespecific regulation of the expression of rat kallikrein gene family members by thyroid hormone. Biochem J 1990; 3: 745]50. 13. Clements JA, Matheson BA, Wines DR, Brady JM, MacDonald RJ, Funder JW. Androgen dependence of specific kallikrein gene family members expressed in rat prostate. J Biol Chem 263: 16132]7. 14. Clements JA, Fuller PJ, McNally M, Nikolaidis I, Funder JW. Estrogen regulation of kallikrein gene expression in the rat anterior pituitary. Endocrinology 1986; 119: 268]73. 15. Malofiejew M. Kallikrein-like activity in human myometrium, placenta and amniotic fluid. Biochem Pharmacol 1973; 222: 123]7. 16. Valdes G, Corthorn J, Scicli AG, Gaete V, Soto J, Ortiz ME, Foradori A, Saed GM. Uterine kallikrein in the early pregnant rat. Biol Reprod 1993; 49: 802]8. 17. Rehbock J, Chondromatidou A, Buchinger P, Hermann A. The B 2 receptor on cultured human decidua cells: release of arachidonic acid by bradykinin. Immunopharmacology 1996; 33: 164]6. 18. Figueroa CD, Gonzalez CD, Muller-Esterl W, Bhoola KD. Cellular localization of human kininogens. In: Bonner G, Fritz H, Scholkens B, Dietze G. eds. Recent Progress in Kinins. Basel: Birkenhauser Verlag, 1992; 38rI: pp. 617]26. 19. Clements JA, Mukhtar A. Glandular kallikreins and prostate-specific antigen are expressed in the human endometrium. J Clin Endoc Metab 1994; 78: 1536]9. 20. Clements JA, Mukhtar A, Ehrlich A, Yap B. Glandular kallikrein gene expression in the human uterus. Braz J Med Biol Res 1994; 27: 1855]63. 21. Espey LL, Tanaka N, Winn V, Okamura H. Increase in ovarian kallikrein activity during ovulation in the gonadotrophin-primed immature rat. J Reprod Fert 1989; 87: 503]8. 22. Gao X, Greenbaum LM, Mahesh VB, Brann DW. Characterization of the kinin system in the ovary during ovulation in the rat. Biol Reprod 47: 945]51.
540
23. Tanaka N, Espey LL, Stacy S, Okamura H. Epostane and indomethacin actions on ovarian kallikrein and plasminogen activator activities during ovulation in the gonadotropin-primed immature rat. Biol Reprod 1992; 46: 665]70.
Pharmacological Research, Vol. 35, No. 6, 1997
24. Hellberg P, Larson L, Olofsson J, Hedin L, Brannstrom M. Stimulatory effects on the ovulatory process in the in vitro-perfused rat ovary. Biol Reprod 1991; 44: 269]74.