- Email: [email protected]
Intercellular communication within the liver has clinical implications
TiPS - january 1983 1Vol. 101
IO
out what RMCE does and how, and may have therapeutic potential. Acknowledgement We thank Drs Be&am, Jacob, Merritt and Sage for helpful discussion. TREWOR J. HALLAM
AND
TIMOTHY J. RINK Snrith Wine & French Reseurch Ltd, The
Frythe. WeJwyn. Herb AL6 9AR. UK.
References 1 Hofmann, F., Nastaincyzk, W., Rohrkasten, A., Schneider, T. and Sieber, M. (1987) Trends P~e~uc~I. Sci. 8.39%398 2 !&d&g, M. (1987) Trends Pkmacol. sci. 8,115-117 3 Rink, T. I. (1988) N&m 334,649650 4 HaIIam, ‘T.. J. and Rink, T. J. (19%) 1. Physiol. (London) 368,131-146 S HaIIam, T. J., Pearson, J. D. and Needham, L. (1988) Biochem. f. 251,243-249 6 HaIIam, T. J. and Rink, T. J. (1985) FEBS Lett. 186.175-179
The liver is an organ of major interest to scientists working in the biomedical field. It plays a key role in the general metabolism of carbohydrates, lipids and amino acids and in the biotransformation of drugs. Although most liver functions are performed in parenchymal cells, other cell types are also present in this organ in&ding Kupffer cells, vascular and endothelial cells, fat storing cells and pit cells. Recent findings have shed some light on the interaction between these cell types. Shukla and coworkers* first showed that platelet activating factor (PAF) stimulated glycogenolysis in perfused liver and phosphoinositide breakdown in isolated liver cells. However, several laboratories were unable to observe any stimulation of glycogenolzis in is&a&d hepatocytes . Since PAF induces vasoconstriction in the perfused liveif*5 in a manner reversible by indometacin and bromophenacyl bromide3, it was suggested that PAP might act by activating cyclooxygenase in non-parenchymal cells and that the cyclooxygenase metabolites could be released and stimulate glycogenolysis in hepatocytes3. Indeed, Altin et al.6 also suggested
7 Hallam, T. J., Jacob, R. and Merritt, J. E. (1988) Biochem. \. 255,179-l&4 8 Andersson, T., DabIgren, C., Pozzan, T., Stendahl, 0. and Lew, D. (1986)Mol. Pharmacol. 30,437-443 9 Merritt, J. E. and HaIIam, T. J. (1988) f. Pot. Chem. 263,6161-6164 10 Brading, A. F. and Sneddon, I’. (1980) Br. 1. Phannacoi. 70,229-240 11 Casteels, R. and Dmogmans, G. (1981) I. Physioi. [London) 317,263-279 12 Putney, J. W. (1986) Cell Calcium 7,1-12 13 Merritt, J. E. and Rink, T. J. (1987) 1. BioL Chem. 262,17362-17369 14 NeguIescu, P. A. and Machen, T. E. (1988) Am. 1. Physiol. 254, C130-140 15 Jacobs, R., MerrItt,J. E., HaIlam, T. J. and Rink, T. J, (1988) Nature 335, 4O-l5 15 Sage, S. 0. and Rink, T. J. (1987) J. BioL Chem. 262, X364-16369 17 Sage,S. 0. (1988)J. Physiol. (London) 396, 43P 18 Benham, C. D. and Tsien, R. W. (1987) Nature 328.275-278 19 Benham, C. D. f. PhysioL (London)abstr. (in pressi 20 von Tscbamer, V., Prod’bom, B., Baggiolini, M. and Reuter, H. (1986) Nature 324.369-372
that the effects of PAF and L-O+ lysophospha~dyl~oline in perfused rat liver (increase in Ca2+ efflux, portal pressure, glycogenolysis and changes in respiration) are mediated by products of the lipoxygenase pathway. Interestingly, the active phorbol ester, phorbol 1%myristate lgacetate (PI&Q, also stimulates glycogenolysis in perfused liver’-“, but not in isolated liver cells” and again this effect can be blocked by indometacin and bromophenyl bromides. It has been reported that PMA increases perfusion pressure
21 Kuno, M. and Gardner, P. (1987) Nature 326,301-304 22 Penner, R., Matthews, G. and Neher, E. (1988) Nature 334,499-504 23 Zschauer, A.,-van Breeman, C., Bukler, F. R. and Nelson, M. T. (1988) Nature 334,70%706 24 Irvine, R. F. and Moore, R. M. (1986) Biocl;em. 1. 240.914-920 25 CrossIey, I., Swarm, K., Chambers, E. and Whitaker, M. (1988) Biochem. 1.252, 252-262 26 Morris, A. P., GaIIacher, D. V., Irvine, R. F. and Peterson, L. C. (19B7) Nqture 330,653-655 27 Cbangya, L.. GaIIacher, D. V., Irvine, R. F., Potter, B. V. L. and Peterson, 0. H. EMBO J. (in press) 28 Berridge, M. J. and Rapp, P. E. (1979) J. Exp. Biol.81,217-279 29 Woods, N. M.. Cuthbertson. K. S. R. and Cobbold, P. H. (1986) &tire 319, 6LlO-602 30 Ambler, S. K., Poenie, M., Tsien, R. Y. and Taylor, P. (1988) 1. Biol. Chem. 263, 1952 31 Berridge, M. J. (198E)j. Physiol. (London) 403,589-599
without altering the production of prostaglandin E2 or &oxo-prostaglandin FI, (Ref. 9). However, it was also possible that the glycogenolytic effect of PAP could be secondary to the hypoxia produced by its vascular effects. Thus, while it was understood that PAF and PMA stimulate glycogenolysis in the liver indirectly, the exact mechanism(s) have until recently remained unclear. Now, however, in an elegant series of publications Casteleijn and coworkers10~‘2-” have begun to unravel the complex cell interactions which lead to this end response. These authors icolated parenchymal cells, Kupffer cells and endothelial cells from the liver to assess the relationship between
Phorbolester PAF aggregatea IgG endotoxin
Q 1969,Ekvier SdencePublishersLid. (UK) Olffi- 6147/89/$o2.m
other mediators
TiPS -January
1989 [Vol. 201
them in the regulation of liver glycogenolysisr2. They demonstrated that: o conditioned media of Kupffer and endothelial liver cells stimulated glycogenolysis in parenchymal cells while conditioned media from cells pretreated with aspirin had no effect”, suggesting involvement of p~staglandins o prostaglandins El, E2 and Dr stimulated glycogenolysis in parenchymal cells, the latter having the greater efficacy12 8 in perfused liver PMA doubled the levels of PGDr in the perfusate’O Q PGD, stimulated glycogenolysis both in perfused liver and isolated parenchymal cellslo. These data suggest that the stimulation of glycogenolysis by P&IA may be mediated by activation of non-parenchymal liver cells to release PGDr, which in turn activates glycogenolysis in parenchymal liver ceils’”
11 pool may contribute to the hypoglycemia observed lateris. These data stress the importance of cellular communication within an organ in determining its response to different stimuli. Obviously, pharmacological manipulation of these processes may give further clues on the mechanism(s) involved and may also be of therapeutic importance. J.
ADOLF0
GARCiA-SthNZ
lnstihto de FisiologiaCelufar, UNAM, Apdo. Postal 762&,04510 Mffxico, DF.
References 1 ShukIa, S. D., Buxton, D. B., Olson, M. S. and Hanahan D. J. (1983) J. BioL Chem. 2S8,18212-18214 2 Fisher, R. A., ShukIa, S. D.. Debuysere, X. S., Hanahan, D. 1;. and Olson, M. S. (1984) j. Piol. Chem. 259,868.5-8688 3 MendIovic, F.. Sorvera. S. and GarciaS%tz, J. A. (1984) Bmi!:cm. Biopkys. Res. Commun. 123,50?-514 4 Charest, R., Prpic, V., !&ton, J. H. end Blackmore, P. F. (1985) Biockem. J. 220, 345-360 5 Buxton, D. B., Fisher, R. A., Hat&an, D. J. and Olson, M. S. (1986) J. Biol. Chem. 261,644-649 6 Altin, J. G.. Dieter, P. and Bygrave, F. t. (1987) Biochem. J. 245.145150 7 Kimura, S., Nagasaki, K., Adachi, I., Yamaguchi, K., Fujiki, H. and Abe, K.
(1984)Biockem. Biophys. Rcs. Commun.
122,1057-1064 8 Garcia-S&z. J. A. and Hem&ndezSotomayor, S. M. T. (1985) Biochem. Biophys. Res. Commun. 132,204-289 9 PateLT. 8. (1987) B&kern.]. 241,S4%%4 10 Casteleijn, E., Kuiper, J., Van Rooij, H. C. J.. Kamps, J. A. A. M., Koster, J. F. and Van Berkel, T. J. C. (1988) Biockem. 1. 2!%, 77-80 11 Corvera,S. and Garcia-S&z, J. A. (1984) Biockem. Biopkys. Kes. Commun. l19z 1128-1133 12 CasteIeijn, E., Kuiper, J., Van Rooij, H. C. I.. UPS, 1. A. A. M., Koster. I. F. and Van Berkei, T. J. C. (1988) I.-&o!. Ckem. 263-2699-2703 13 Casteleijn; E., Kuiper, J., Van Rooij, H. C. I., Koster, J- F. and Van Berkel, T. J. C. (1988) Biockem. j.282,601-685 14 Casteleijn, E., Kuiper, J., Van Rooij, Ii. C. J.. Kamps, J. A A. M., Koster, J. F_ and Van Berkel, T. J. C. (19S8) J_ 8ieL Ckem. 263,6953-69% 15 Buxton. D. B.. Hanahan. D. 1. and Olson. M. S. -(1984) J. Sidr. them. 2!$ 13758-13761 16 Fisher, R. A., Robertson, S. M. and Olson, M. S. (1987) f. Biol. Ckem. 262, 4631-4638 17 Csmussi, G.. TetIn, C., Deregibus, W C., Bussohno, E, SegoIini, G. and VerceLn-. A. (1982) l.~mmunol. l28, 86-94 18 KnowIes, R. G., Beewr~. J- and Pogson, C. I. (1986) Btockem. Pkamrrrol. 35, 4043448
U-46619: 9,11-dideoxy-llu-apoxymethanoprostagIandin Fr=
Progesterone derivatives that cii@i&sreceptor Certain derivatives of progesterone interact with the ‘digitalis receptor‘, i.e. the cardiac glycoside recognition site of Na+/K+ATPase, a vital and universal membrane enzyme1-5. These steroids inhibit the purified enzyme and the sodium pump (“Rb uptake) in isolated cells and tissues. However, some pregnanes, like progesterone itself, are primarily cardiodepressar&, and others, predominantly cardiostimulant~~‘. The pregnanes appear to act concomitantly at another site, presumably intracellular, which mediates cardiodepression. This countervailing cardiodepressive action may constitute the basis for an increased margin of safety reported for the pregnanes’-‘. Positive inotropyl cardiodepression balance Progesterone itself is a depressant on isolated cardiac tissues from several species3p6. Chlormadinone acetate (CMA), one of
the most potent of the digitaloid prepanes (Fig. 1, Table I) inhibits Na /K+-ATPase and the sodium pump yet elicits cardiodepression in isolated tissue4s and in the anesthetized cats. A prevalent hypothesis causally relates the positive inotropic effect of the cardiac glycosides to elevated levels of intracellular Ca2+. The increase in intracellular Na+, as a consequence of membrane sodium pump irnibition is believed to promoe net accumulation of calcium via a Na+-Ca*+ exchange process”. CMA, progesterone and certain steroids, related structurally inhibit Na+/K’-ATPase and the sodium pump (%Rb uptake in red blood cells and cardiac tissues) but, in contrast to the cardiac glycosides, fail to elevate ~~ace~~ Ca2+ (Ref. 3), suggesting that cardiodepression by the preg nanes is mediated by a mechanism which is distinct from inhibition of the enzyme and which antagonizes the rise in cytoplasmic
IO
out what RMCE does and how, and may have therapeutic potential. Acknowledgement We thank Drs Be&am, Jacob, Merritt and Sage for helpful discussion. TREWOR J. HALLAM
AND
TIMOTHY J. RINK Snrith Wine & French Reseurch Ltd, The
Frythe. WeJwyn. Herb AL6 9AR. UK.
References 1 Hofmann, F., Nastaincyzk, W., Rohrkasten, A., Schneider, T. and Sieber, M. (1987) Trends P~e~uc~I. Sci. 8.39%398 2 !&d&g, M. (1987) Trends Pkmacol. sci. 8,115-117 3 Rink, T. I. (1988) N&m 334,649650 4 HaIIam, ‘T.. J. and Rink, T. J. (19%) 1. Physiol. (London) 368,131-146 S HaIIam, T. J., Pearson, J. D. and Needham, L. (1988) Biochem. f. 251,243-249 6 HaIIam, T. J. and Rink, T. J. (1985) FEBS Lett. 186.175-179
The liver is an organ of major interest to scientists working in the biomedical field. It plays a key role in the general metabolism of carbohydrates, lipids and amino acids and in the biotransformation of drugs. Although most liver functions are performed in parenchymal cells, other cell types are also present in this organ in&ding Kupffer cells, vascular and endothelial cells, fat storing cells and pit cells. Recent findings have shed some light on the interaction between these cell types. Shukla and coworkers* first showed that platelet activating factor (PAF) stimulated glycogenolysis in perfused liver and phosphoinositide breakdown in isolated liver cells. However, several laboratories were unable to observe any stimulation of glycogenolzis in is&a&d hepatocytes . Since PAF induces vasoconstriction in the perfused liveif*5 in a manner reversible by indometacin and bromophenacyl bromide3, it was suggested that PAP might act by activating cyclooxygenase in non-parenchymal cells and that the cyclooxygenase metabolites could be released and stimulate glycogenolysis in hepatocytes3. Indeed, Altin et al.6 also suggested
7 Hallam, T. J., Jacob, R. and Merritt, J. E. (1988) Biochem. \. 255,179-l&4 8 Andersson, T., DabIgren, C., Pozzan, T., Stendahl, 0. and Lew, D. (1986)Mol. Pharmacol. 30,437-443 9 Merritt, J. E. and HaIIam, T. J. (1988) f. Pot. Chem. 263,6161-6164 10 Brading, A. F. and Sneddon, I’. (1980) Br. 1. Phannacoi. 70,229-240 11 Casteels, R. and Dmogmans, G. (1981) I. Physioi. [London) 317,263-279 12 Putney, J. W. (1986) Cell Calcium 7,1-12 13 Merritt, J. E. and Rink, T. J. (1987) 1. BioL Chem. 262,17362-17369 14 NeguIescu, P. A. and Machen, T. E. (1988) Am. 1. Physiol. 254, C130-140 15 Jacobs, R., MerrItt,J. E., HaIlam, T. J. and Rink, T. J, (1988) Nature 335, 4O-l5 15 Sage, S. 0. and Rink, T. J. (1987) J. BioL Chem. 262, X364-16369 17 Sage,S. 0. (1988)J. Physiol. (London) 396, 43P 18 Benham, C. D. and Tsien, R. W. (1987) Nature 328.275-278 19 Benham, C. D. f. PhysioL (London)abstr. (in pressi 20 von Tscbamer, V., Prod’bom, B., Baggiolini, M. and Reuter, H. (1986) Nature 324.369-372
that the effects of PAF and L-O+ lysophospha~dyl~oline in perfused rat liver (increase in Ca2+ efflux, portal pressure, glycogenolysis and changes in respiration) are mediated by products of the lipoxygenase pathway. Interestingly, the active phorbol ester, phorbol 1%myristate lgacetate (PI&Q, also stimulates glycogenolysis in perfused liver’-“, but not in isolated liver cells” and again this effect can be blocked by indometacin and bromophenyl bromides. It has been reported that PMA increases perfusion pressure
21 Kuno, M. and Gardner, P. (1987) Nature 326,301-304 22 Penner, R., Matthews, G. and Neher, E. (1988) Nature 334,499-504 23 Zschauer, A.,-van Breeman, C., Bukler, F. R. and Nelson, M. T. (1988) Nature 334,70%706 24 Irvine, R. F. and Moore, R. M. (1986) Biocl;em. 1. 240.914-920 25 CrossIey, I., Swarm, K., Chambers, E. and Whitaker, M. (1988) Biochem. 1.252, 252-262 26 Morris, A. P., GaIIacher, D. V., Irvine, R. F. and Peterson, L. C. (19B7) Nqture 330,653-655 27 Cbangya, L.. GaIIacher, D. V., Irvine, R. F., Potter, B. V. L. and Peterson, 0. H. EMBO J. (in press) 28 Berridge, M. J. and Rapp, P. E. (1979) J. Exp. Biol.81,217-279 29 Woods, N. M.. Cuthbertson. K. S. R. and Cobbold, P. H. (1986) &tire 319, 6LlO-602 30 Ambler, S. K., Poenie, M., Tsien, R. Y. and Taylor, P. (1988) 1. Biol. Chem. 263, 1952 31 Berridge, M. J. (198E)j. Physiol. (London) 403,589-599
without altering the production of prostaglandin E2 or &oxo-prostaglandin FI, (Ref. 9). However, it was also possible that the glycogenolytic effect of PAP could be secondary to the hypoxia produced by its vascular effects. Thus, while it was understood that PAF and PMA stimulate glycogenolysis in the liver indirectly, the exact mechanism(s) have until recently remained unclear. Now, however, in an elegant series of publications Casteleijn and coworkers10~‘2-” have begun to unravel the complex cell interactions which lead to this end response. These authors icolated parenchymal cells, Kupffer cells and endothelial cells from the liver to assess the relationship between
Phorbolester PAF aggregatea IgG endotoxin
Q 1969,Ekvier SdencePublishersLid. (UK) Olffi- 6147/89/$o2.m
other mediators
TiPS -January
1989 [Vol. 201
them in the regulation of liver glycogenolysisr2. They demonstrated that: o conditioned media of Kupffer and endothelial liver cells stimulated glycogenolysis in parenchymal cells while conditioned media from cells pretreated with aspirin had no effect”, suggesting involvement of p~staglandins o prostaglandins El, E2 and Dr stimulated glycogenolysis in parenchymal cells, the latter having the greater efficacy12 8 in perfused liver PMA doubled the levels of PGDr in the perfusate’O Q PGD, stimulated glycogenolysis both in perfused liver and isolated parenchymal cellslo. These data suggest that the stimulation of glycogenolysis by P&IA may be mediated by activation of non-parenchymal liver cells to release PGDr, which in turn activates glycogenolysis in parenchymal liver ceils’”
11 pool may contribute to the hypoglycemia observed lateris. These data stress the importance of cellular communication within an organ in determining its response to different stimuli. Obviously, pharmacological manipulation of these processes may give further clues on the mechanism(s) involved and may also be of therapeutic importance. J.
ADOLF0
GARCiA-SthNZ
lnstihto de FisiologiaCelufar, UNAM, Apdo. Postal 762&,04510 Mffxico, DF.
References 1 ShukIa, S. D., Buxton, D. B., Olson, M. S. and Hanahan D. J. (1983) J. BioL Chem. 2S8,18212-18214 2 Fisher, R. A., ShukIa, S. D.. Debuysere, X. S., Hanahan, D. 1;. and Olson, M. S. (1984) j. Piol. Chem. 259,868.5-8688 3 MendIovic, F.. Sorvera. S. and GarciaS%tz, J. A. (1984) Bmi!:cm. Biopkys. Res. Commun. 123,50?-514 4 Charest, R., Prpic, V., !&ton, J. H. end Blackmore, P. F. (1985) Biockem. J. 220, 345-360 5 Buxton, D. B., Fisher, R. A., Hat&an, D. J. and Olson, M. S. (1986) J. Biol. Chem. 261,644-649 6 Altin, J. G.. Dieter, P. and Bygrave, F. t. (1987) Biochem. J. 245.145150 7 Kimura, S., Nagasaki, K., Adachi, I., Yamaguchi, K., Fujiki, H. and Abe, K.
(1984)Biockem. Biophys. Rcs. Commun.
122,1057-1064 8 Garcia-S&z. J. A. and Hem&ndezSotomayor, S. M. T. (1985) Biochem. Biophys. Res. Commun. 132,204-289 9 PateLT. 8. (1987) B&kern.]. 241,S4%%4 10 Casteleijn, E., Kuiper, J., Van Rooij, H. C. J.. Kamps, J. A. A. M., Koster, J. F. and Van Berkel, T. J. C. (1988) Biockem. 1. 2!%, 77-80 11 Corvera,S. and Garcia-S&z, J. A. (1984) Biockem. Biopkys. Kes. Commun. l19z 1128-1133 12 CasteIeijn, E., Kuiper, J., Van Rooij, H. C. I.. UPS, 1. A. A. M., Koster. I. F. and Van Berkei, T. J. C. (1988) I.-&o!. Ckem. 263-2699-2703 13 Casteleijn; E., Kuiper, J., Van Rooij, H. C. I., Koster, J- F. and Van Berkel, T. J. C. (1988) Biockem. j.282,601-685 14 Casteleijn, E., Kuiper, J., Van Rooij, Ii. C. J.. Kamps, J. A A. M., Koster, J. F_ and Van Berkel, T. J. C. (19S8) J_ 8ieL Ckem. 263,6953-69% 15 Buxton. D. B.. Hanahan. D. 1. and Olson. M. S. -(1984) J. Sidr. them. 2!$ 13758-13761 16 Fisher, R. A., Robertson, S. M. and Olson, M. S. (1987) f. Biol. Ckem. 262, 4631-4638 17 Csmussi, G.. TetIn, C., Deregibus, W C., Bussohno, E, SegoIini, G. and VerceLn-. A. (1982) l.~mmunol. l28, 86-94 18 KnowIes, R. G., Beewr~. J- and Pogson, C. I. (1986) Btockem. Pkamrrrol. 35, 4043448
U-46619: 9,11-dideoxy-llu-apoxymethanoprostagIandin Fr=
Progesterone derivatives that cii@i&sreceptor Certain derivatives of progesterone interact with the ‘digitalis receptor‘, i.e. the cardiac glycoside recognition site of Na+/K+ATPase, a vital and universal membrane enzyme1-5. These steroids inhibit the purified enzyme and the sodium pump (“Rb uptake) in isolated cells and tissues. However, some pregnanes, like progesterone itself, are primarily cardiodepressar&, and others, predominantly cardiostimulant~~‘. The pregnanes appear to act concomitantly at another site, presumably intracellular, which mediates cardiodepression. This countervailing cardiodepressive action may constitute the basis for an increased margin of safety reported for the pregnanes’-‘. Positive inotropyl cardiodepression balance Progesterone itself is a depressant on isolated cardiac tissues from several species3p6. Chlormadinone acetate (CMA), one of
the most potent of the digitaloid prepanes (Fig. 1, Table I) inhibits Na /K+-ATPase and the sodium pump yet elicits cardiodepression in isolated tissue4s and in the anesthetized cats. A prevalent hypothesis causally relates the positive inotropic effect of the cardiac glycosides to elevated levels of intracellular Ca2+. The increase in intracellular Na+, as a consequence of membrane sodium pump irnibition is believed to promoe net accumulation of calcium via a Na+-Ca*+ exchange process”. CMA, progesterone and certain steroids, related structurally inhibit Na+/K’-ATPase and the sodium pump (%Rb uptake in red blood cells and cardiac tissues) but, in contrast to the cardiac glycosides, fail to elevate ~~ace~~ Ca2+ (Ref. 3), suggesting that cardiodepression by the preg nanes is mediated by a mechanism which is distinct from inhibition of the enzyme and which antagonizes the rise in cytoplasmic