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Adrenomedullin and proadrenomedullin N-terminal 20 peptide induce histamine release from rat peritoneal mast cell
Regulatory Peptides 101 Ž2001. 163–168 www.elsevier.comrlocaterregpep
Adrenomedullin and proadrenomedullin N-terminal 20 peptide induce histamine release from rat peritoneal mast cell Mitsunobu Yoshida a , Hiroshi Yoshida a , Kiyoyuki Kitaichi b, Kenju Hiramatsu a , Tomoki Kimura a , Yasushi Ito a , Hiroaki Kume a , Kenichi Yamaki a , Ryujiro Suzuki c , Eiji Shibata b, Takaaki Hasegawa b, Kenzo Takagi b,) b
a Internal Medicine II, Nagoya UniÕersity School of Medicine, 65 Tsuruma-Cho, Showa, Nagoya 466-8550, Japan Department of Medical Technology, Nagoya UniÕersity School of Health Sciences, 1-1-20 Daikominami, Higashi, Nagoya 461-8673, Japan c Laboratory Medicine, Nagoya UniÕersity School of Medicine, 65 Tsuruma-Cho, Showa, Nagoya 466-8550, Japan
Received 28 December 2000; received in revised form 18 May 2001; accepted 22 May 2001
Abstract Adrenomedullin ŽADM.-induced histamine release from rat peritoneal mast cells was investigated. We compared the ability of full-length ADM to induce histamine release to the fragments ADM-Ž1–25. and ADM-Ž22–52., as well as proadrenomedullin N-terminal 20 peptide ŽPAMP.. ADM Ž10y8 to 10y5 M. and PAMP Ž10y8 to 10y5 M. dose-dependently increased histamine release from peritoneal mast cell preparations. The effect of ADM-Ž1–25. was similar to ADM, whereas ADM-Ž22–52. did not show any effects. These data suggest the relative importance of the ADM C-terminal fragment, which contains a six-membered ring structure. Histamine release, induced by ADM, was significantly and dose-dependently inhibited by the addition of ADM-Ž22–52. Ž10y5 M., Ca2q Ž0.5 to 2.0 mM., and benzalkonium chloride Ž3 to 7 mM., a selective inhibitor of Gi type G proteins. In contrast, PAMP Ž10y5 M.-induced histamine release was not inhibited by Ca2q. These results suggest that ADM induce histamine release via a putative ADM receptor in a manner sensitive to Gi-protein function and extracellular Ca2q concentration, and that PAMP might produce its effect by a different mechanism than ADM. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Adrenomedullin ŽADM.; Proadrenomedullin N-terminal 20 peptide ŽPAMP.; Mast cells; Histamine release; Extracellular Ca2q; G protein
1. Introduction Adrenomedullin ŽADM. is a novel 52-amino-acid peptide that was originally isolated from pheochromocytoma by monitoring the capacity of extracted cellular fractions to elevate cyclic adenosine monophosphate ŽcAMP. in platelets w1x. ADM and another unique 20 amino acid sequence, designated proadrenomedullin N-terminal 20 peptide ŽPAMP., are enzymatically cleaved from a 185amino-acid precursor termed preproadrenomedullin w1x. Considering the presence of a common six-membered ring structure and C-terminal amidation, it is believed that ADM belongs to the calcitonin gene related peptide ŽCGRP.ramylin superfamily w2,3x. Moreover, there is slight amino acid homology with this superfamily w2,3x.
) Corresponding author. Tel.: q81-52-719-3008, 1552; fax: q81-52719-3009. E-mail address: [email protected] ŽK. Takagi..
ADM is abundantly present in several tissues, as well as in plasma w1,2,4x. Plasma level of ADM are elevated in various diseases states, including congestive heart failure w5,6x, hypertension w6,7x, renal failure w6x, septic shock w8,9x, diabetes w10x, asthma w11x and pulmonary hypertension w12x, suggesting its biological activities. Indeed, it has been reported that ADM has potent and long-lasting hypotensive w2,13x and vasodilator activities w14–16x. ADM gene expression has been found in peritoneal macrophages w17–19x, the macrophage cell line RAW 264.7 w18x, as well as peripheral granulocytes w19x, lymphocytes w19x, and monocytes w19x. These findings suggest a critical role for ADM at the site of inflammation in disease states such as asthma. Moreover, endotoxin and other inflammatory cytokines such as interferon-g and tumor necrosis factor-a stimulate the release of ADM from these immune cell-types w17–19x. Thus, it is hypothesized that ADM might be secreted from these immune cells into the blood circulation during sepsis, probably causing hypotension w2x. However, it remains unclear how ADM influences the function of
0167-0115r01r$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 7 - 0 1 1 5 Ž 0 1 . 0 0 2 8 3 - X
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inflammatory cells, including mast cells, which are important for immune response at local inflammatory sites. In the present study, we have investigated the effect of ADM, ADM fragments wADM-Ž1–25. and ADM-Ž22–52.x, PAMP, and CGRP on histamine release from rat peritoneal mast cells.
2. Materials and methods 2.1. Animals and drugs Male Wistar rats Ž300–400g. were purchased from Japan SLC ŽShizuoka, Japan.. Animals were housed in a temperature- Ž22–24 8C., humidity- Ž55 " 5%. and lightŽ12 h light–dark cycle; lights on at 07:00.-regulated room with food and water ad libitum for at least 3 days before the experiments. The procedures involving animals and their care were conducted in accordance with AGuiding Principles for the Care and Use of Laboratory AnimalsB of Nagoya University, Japan. hADM, hPAMP, hADM-Ž1– 25., hADM-Ž22–52., hCGRP were purchased from Peptide Institute ŽOsaka, Japan.. All other chemical were obtained commercially and used without further purification. Peptides were dissolved in Ca2q- and Mg 2q-free Tyrode’s solution containing 20-mM HEPES buffer. 2.2. Crude peritoneal mast cells preparation Under pentobarbital anesthesia, the peritoneal cavity of rat was washed with 10 ml of Ca2q- and Mg 2q-free Tyrode’s solution, containing 0.1% Žweightrvolume. bovine serum albumin ŽBSA. and 10 unitsrml sodium heparin. After gentle massage of the abdomen for 3 min, peritoneal exudate cells ŽPEC. in fluid were obtained. Collected PEC fluid was washed three times with Ca2qand Mg 2q-free Tyrode’s solution, containing 0.1% Žwrv. BSA and 10-unitsrml sodium heparin by centrifugation Ž1200 rpm, 4 8C, 10 min.. The pellets were then resuspended in ice-cold Ca2q-, Mg 2q-free Tyrode’s solution, containing 20 mM HEPES buffer at a concentration of 5 = 10 6 mast cellsrml.
an ice-cold bath and then centrifuged at 2500 rpm, 4 8C for 10 min, and the supernatant was then collected. To determine the effects of ADM-Ž22–52. on the histamine release induced by ADM, ADM-Ž22–52. Ž10y5 M. was added to PEC fluid just before adding ADM Ž10y5 M.. To determine the effects of extracellular Ca2q on the histamine release induced by the peptides, the desired concentrations of Ca2q were added immediately before the pre-incubation period, after which samples were incubated with ADM Ž10y5 M. or PAMP Ž10y6 M.. The concentrations of Ca2q were selected Ž0.5–2 mM. to inhibit peptide-induced histamine release, as has been described elsewhere w20,21x. To assess the effect of benzalkonium chloride, desired concentrations of benzalkonium chloride were added before the pre-incubation period, after which samples were incubated with ADM Ž10y5 M.. The concentrations of benzalkonium chloride Ž1–7 mM. were chosen to selectively inhibit the activity of G protein of the Gi type w20,22x. Collected supernatants were kept at y80 8C until analysis. In all experiments, the amount of lactate dehydrogenase ŽLDH. in the supernatants was determined before and after the incubation in order to verify cell viability. 2.4. Measurement of histamine release from peritoneal mast cells The amount of supernatant histamine was determined according to the method of May et al. w23x. The extracted histamine was determined by high performance liquid chromatography. The mobile phase was composed of 40% methanol in water containing 0.042-M acetate buffer, pH 4.0. The chromatography was performed on a YMC Packed Column A-302 ŽYamamura Chemical Laboratories, Kyoto, Japan.. The flow rate was 1 mlrmin and the fluorescence was monitored at 460 nm with excitation at 360 nm. Total histamine release was determined in intact PEC fluid after lysis by boiling for 5 min. Spontaneous histamine release was less than 7% throughout all experiments.
2.3. Cell incubation Test tubes, each containing 0.9 ml of the PEC fluid, were pre-incubated for 10 min at 37 8C. Following this, 0.1 ml of each peptide solution was added to the medium. In order to estimate the time-course effect of ADM, the fragments of ADM, CGRP and PAMP on histamine release, PEC fluid was incubated for different times Ž0.5–15 min. with 10y6 M of ADM. To determine the dose-dependent effect of ADM and PAMP on histamine release, PEC fluid was incubated for 10 min with different concentrations of peptide solution Ž10y8 to 10y5 M.. After finishing the experiments, all test tubes were immediately placed in
Fig. 1. Time-course effect of ADM Ž10y6 M. on histamine release from rat peritoneal mast cells. Each point represents the mean"S.D. of three independent experiments.
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Fig. 2. ŽA. Dose-dependent effects of ADM Ž`., PAMP Žv ., and CGRP Ž'. on histamine release from rat peritoneal mast cell. Each point represents the mean " S.D. of four to eight independent experiments. ŽB. Dose-dependent effects of ADM-Ž1–25. ŽI. and ADM-Ž22–52. ŽB. on histamine release from rat peritoneal mast cell. Each point represents the mean " S.D. of eight independent experiments.
2.5. Statistical analysis Data are expressed as mean " S.D. of the net percent of total histamine release. Statistical analyses were performed using StatView ŽAbacus Concept, Barkeley, CA, USA..
3. Results As shown in Fig. 1, ADM Ž10y6 M. stimulated histamine release from rat peritoneal mast cell very rapidly and had a maximal effect within 0.5 min. Based on this
result, we selected 10 min as an incubation period for subsequent experiments. PAMP-induced histamine release also reached maximum within 10 min Ždata not shown.. Both ADM and PAMP dose-dependently induced histamine release from rat peritoneal mast cells ŽFig. 2A.. At the highest concentration tested Ž10y5 M., histamine release induced by ADM and PAMP was 49.4 " 3.2% and 47.0 " 7.0%, respectively. It should be noted that LDH release into the supernatants from mast cells treated with ADM Ž10y5 M. and PAMP Ž10y5 M. was less than 8% above background, which was not significantly different from control Ždata not shown., indicating that ADM in-
Fig. 3. ŽA. Effects of extracellular Ca2q on histamine release from rat peritoneal mast cells induced by ADM Ž10y6 M, `. and PAMP Ž10y5 M, v .. Each point represents the mean " S.D. of four and eight independent experiments, respectively. ŽB. Effects of benzalkonium chloride on histamine release from rat peritoneal mast cells induced by ADM Ž10y6 M, `.. Each point represents the mean " S.D. of four independent experiments, a p - 0.01 vs. ADM Ž10y6 M. ŽScheffe’s post-hoc test, followed by one-way ANOVA..
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duced histamine release was not associated with cytotoxicity. In contrast, CGRP, at concentrations up to 10y5 M, did not increase histamine release ŽFig. 2A.. ADM-Ž1–25. showed almost the same ability to induce histamine release as did full-length ADM, whereas, ADMŽ22–52. had no effect ŽFig. 2B.. At the highest concentration tested Ž10y5 M., histamine release induced by ADMŽ1–25. and ADM-Ž22–52. amounted to 53.7 " 4.0% and 12.4 " 4.3%, respectively. ADM Ž10y5 M.-induced histamine release was significantly inhibited by ADM-Ž22–52. Ž10y5 M. w71 " 7.2% of ADM Ž10y5 M.-induced histamine release, p - 0.05, data not shownx. As shown in Fig. 3A, addition of Ca2q into the assay buffer dose-dependently inhibited the histamine release induced by ADM Ž10y5 M. at a concentration of 0.5 mM or higher. In contrast, the highest extracellular calcium concentration tested Ž2 mM. failed to inhibit PAMP Ž10y5 M.-induced histamine release. Histamine release induced by ADM Ž10y6 M. and PAMP Ž10y5 M. in the presence of Ca2q Ž2 mM. was 2.4 " 0.6% and 49.0 " 2.6%, respectively. Fig. 3B shows the effects of benzalkonium chloride on histamine release from rat peritoneal mast cells. Indeed, benzalkonium chloride dose-dependently inhibited the histamine release induced by ADM Ž10y6 M..
4. Discussion In the present study, ADM and PAMP dose-dependently induced histamine release from rat peritoneal mast cells. The potency of ADM and PAMP in this regard is similar to that of other endogenous peptides, such as nociceptin w21x, midkine w20x, pituitary adenylate cyclase activating peptide ŽPACAP. w24x, substance P w25–27x, tachykinins w28x and neuropeptide Y w29x. The effect of ADM-Ž1–25. was similar to ADM, whereas, ADM-Ž22– 52. and CGRP failed to induce histamine release. ADMinduced histamine release was inhibited by ADM-Ž22–52., extracellular Ca2q and benzalkonium chloride, a selective inhibitor of G protein of the Gi type w20,22x. Similar to ADM, PAMP also induced histamine release from mast cells, although the effect of PAMP was insensitive to Ca2q. Taken together, these results suggest that ADM and PAMP, via different mechanisms, might play an important role in immune response. It is likely that a fragment of ADM, namely ADM-Ž16– . 21 , might be important for the pharmacological effects of ADM w2,30x. This fragment forms a six-membered ring structure that is conserved in different species Že.g., human, pig, bovine, rat, mouse, dog. w30x. For example, like full-length ADM, ADM-Ž15–22. possesses vasodilator activity, whereas, ADM-Ž22–52. and ADM-Ž40–52. do not w30x. In the present study, ADM-Ž1–25. showed the same effect as full-length ADM on histamine release, whereas
ADM-Ž22–52. did not induce histamine release by itself. Moreover, induction of histamine release from rat peritoneal mast cells by ADM occurred rapidly and reached its maximum effect within 30 seconds after the challenge. This is in contrast to Ig-E-induced histamine release from mast cells, which takes several minutes to reach its peak response w32,33x. Taken together, these results suggest the involvement of a putative ADM receptor on mast cells that mediates the effect on histamine release. A similar six-membered ring structure is also conserved in the CGRP families ŽCGRP, ADM, amylin.. Thus, there is a possibility that ADM and CGRP induced histamine release via a putative CGRP receptor. Indeed, CGRP stimulates the release of histamine from bronchoalveolar lavage in human w34x and from pig dural mast cells w35x, but not pig peritoneal mast cells w35x. Very recently, several ADM receptors, as well as CGRP receptors, have been cloned w2,3x. For example, McLatchie et al. w36x have demonstrated that the pharmacological profile of the calcitonin receptor-like receptor ŽCRLR. is altered by its association with the receptor-activity modifying proteins ŽRAMPs., with CRLRrRAMP-1 acting as the CGRP receptor and CRLRrRAMP-2 as the ADM receptor. Accordingly, it is of interest to evaluate more precisely the pharmacological characterization of a putative ADM receptor on mast cells. In the current experiments, CGRP at concentrations up to 10y5 M, did not induce histamine release, and this is partially consistent with previous evidence from pig peritoneal mast cells w35x. Alternatively, it has been reported that ADM-Ž22–52. has an ability to antagonize the effect of ADM by blocking the ADM receptor w2,31x. Indeed, in our model, ADM-Ž22–52. inhibited ADM-induced histamine release. Taken together, it is likely that the ADM receptor, rather than the CGRP receptor, may play an important role in ADM-induced histamine release from rat peritoneal mast cells, although further studies, including species- and origin-differences, are necessary. It has been reported that inhibition of Gi protein activity, or addition of extracellular Ca2q, can inhibit histamine release from peritoneal mast cells induced by midkine w20x, substance P w26x and nociceptin w21x. Interestingly, ADMinduced histamine release was inhibited by the selective Gi protein inhibitor benzalkonium chloride w20,22x and extracellular Ca2q, suggesting that it is regulated by Ca2q- and Gi-protein-sensitive pathways. Thus far, three molecularly defined receptors for ADM have been identified; calcitonin receptor-like receptor w37x, L1 orphan receptor w38x, and RDC-1 receptor w39x. These ADM receptors are all coupled to G proteins of the Gs type and adenylyl cyclase, which presumably stimulates accumulation of cAMP w2,3x. Further studies are necessary to elucidate the underlying mechanisms that regulate ADM-induced histamine release, including the potential contribution of the Gs-adenylyl cyclase-cAMP pathway. It should be noted that some peptides, such as neuropeptide Y w40x, substance P w29x and pituitary adenylate
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activating polypeptide ŽPACAP. w24x, might stimulate the release of mediators from mast cells via non-receptor mediated mechanisms w33,41x. For example, Grundemar et al. w42x demonstrated that the rank order of potency of neuropeptide Y and its fragments, to stimulate histamine release from mast cell, did not correlate with any previously known or postulated affinity for neuropeptide Y receptors. Moreover, similar evidence was observed in PACAP-stimulated release of histamine w25x and serotonin w41x from rat peritoneal mast cells. Seeback et al. w41x demonstrated that PACAP-stimulated serotonin-release was sensitive to either the phospholipase C inhibitors U73122 and D906, the protein kinase C inhibitor staurosporine, or the lipoxygenase inhibitor nordihydroxyguaiaretic acid, suggesting the involvement of multiple signaling pathways. It will, thus, be of interest to further elucidate whether or not ADM and PAMP act on their putative receptors to stimulate histamine release. The receptor for PAMP and PAMP-mediated cellular signaling has not been fully identified. Very recently, Ohinata et al. w43x demonstrated that PAMP shows affinity for bombesin receptor families in the nmol range in bombesin receptor-transfected BALB 3T3 cells. Interestingly, bombesin itself can induce histamine release from mast cells w44,45x. Accordingly, it is possible that PAMP is able to induce histamine release via a bombesin receptor. Further studies should be carried out to determine the underlying mechanism of action of PAMP. In conclusion, ADM and PAMP are capable of inducing histamine release from rat peritoneal mast cells. It is still uncertain whether the ADM-concentrations used ŽnM to mM range. in this study is physiologically relevant, since plasma levels of ADM are of the pM range w2x. Sensory neuronal terminals w2,35x and immune cells w17–19x, however, are good candidates for supplying ADM at the site of inflammation, and might elevate local ADM concentrations to a high level. Thus, ADM receptor antagonists acting on mast cells could inhibit the ADM-induced histamine release, potentially inhibiting inflammation.
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Acknowledgements We would like to thank Professor Tetsuo Hayakawa for his encouragement throughout this study.
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Adrenomedullin and proadrenomedullin N-terminal 20 peptide induce histamine release from rat peritoneal mast cell Mitsunobu Yoshida a , Hiroshi Yoshida a , Kiyoyuki Kitaichi b, Kenju Hiramatsu a , Tomoki Kimura a , Yasushi Ito a , Hiroaki Kume a , Kenichi Yamaki a , Ryujiro Suzuki c , Eiji Shibata b, Takaaki Hasegawa b, Kenzo Takagi b,) b
a Internal Medicine II, Nagoya UniÕersity School of Medicine, 65 Tsuruma-Cho, Showa, Nagoya 466-8550, Japan Department of Medical Technology, Nagoya UniÕersity School of Health Sciences, 1-1-20 Daikominami, Higashi, Nagoya 461-8673, Japan c Laboratory Medicine, Nagoya UniÕersity School of Medicine, 65 Tsuruma-Cho, Showa, Nagoya 466-8550, Japan
Received 28 December 2000; received in revised form 18 May 2001; accepted 22 May 2001
Abstract Adrenomedullin ŽADM.-induced histamine release from rat peritoneal mast cells was investigated. We compared the ability of full-length ADM to induce histamine release to the fragments ADM-Ž1–25. and ADM-Ž22–52., as well as proadrenomedullin N-terminal 20 peptide ŽPAMP.. ADM Ž10y8 to 10y5 M. and PAMP Ž10y8 to 10y5 M. dose-dependently increased histamine release from peritoneal mast cell preparations. The effect of ADM-Ž1–25. was similar to ADM, whereas ADM-Ž22–52. did not show any effects. These data suggest the relative importance of the ADM C-terminal fragment, which contains a six-membered ring structure. Histamine release, induced by ADM, was significantly and dose-dependently inhibited by the addition of ADM-Ž22–52. Ž10y5 M., Ca2q Ž0.5 to 2.0 mM., and benzalkonium chloride Ž3 to 7 mM., a selective inhibitor of Gi type G proteins. In contrast, PAMP Ž10y5 M.-induced histamine release was not inhibited by Ca2q. These results suggest that ADM induce histamine release via a putative ADM receptor in a manner sensitive to Gi-protein function and extracellular Ca2q concentration, and that PAMP might produce its effect by a different mechanism than ADM. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Adrenomedullin ŽADM.; Proadrenomedullin N-terminal 20 peptide ŽPAMP.; Mast cells; Histamine release; Extracellular Ca2q; G protein
1. Introduction Adrenomedullin ŽADM. is a novel 52-amino-acid peptide that was originally isolated from pheochromocytoma by monitoring the capacity of extracted cellular fractions to elevate cyclic adenosine monophosphate ŽcAMP. in platelets w1x. ADM and another unique 20 amino acid sequence, designated proadrenomedullin N-terminal 20 peptide ŽPAMP., are enzymatically cleaved from a 185amino-acid precursor termed preproadrenomedullin w1x. Considering the presence of a common six-membered ring structure and C-terminal amidation, it is believed that ADM belongs to the calcitonin gene related peptide ŽCGRP.ramylin superfamily w2,3x. Moreover, there is slight amino acid homology with this superfamily w2,3x.
) Corresponding author. Tel.: q81-52-719-3008, 1552; fax: q81-52719-3009. E-mail address: [email protected] ŽK. Takagi..
ADM is abundantly present in several tissues, as well as in plasma w1,2,4x. Plasma level of ADM are elevated in various diseases states, including congestive heart failure w5,6x, hypertension w6,7x, renal failure w6x, septic shock w8,9x, diabetes w10x, asthma w11x and pulmonary hypertension w12x, suggesting its biological activities. Indeed, it has been reported that ADM has potent and long-lasting hypotensive w2,13x and vasodilator activities w14–16x. ADM gene expression has been found in peritoneal macrophages w17–19x, the macrophage cell line RAW 264.7 w18x, as well as peripheral granulocytes w19x, lymphocytes w19x, and monocytes w19x. These findings suggest a critical role for ADM at the site of inflammation in disease states such as asthma. Moreover, endotoxin and other inflammatory cytokines such as interferon-g and tumor necrosis factor-a stimulate the release of ADM from these immune cell-types w17–19x. Thus, it is hypothesized that ADM might be secreted from these immune cells into the blood circulation during sepsis, probably causing hypotension w2x. However, it remains unclear how ADM influences the function of
0167-0115r01r$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 7 - 0 1 1 5 Ž 0 1 . 0 0 2 8 3 - X
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inflammatory cells, including mast cells, which are important for immune response at local inflammatory sites. In the present study, we have investigated the effect of ADM, ADM fragments wADM-Ž1–25. and ADM-Ž22–52.x, PAMP, and CGRP on histamine release from rat peritoneal mast cells.
2. Materials and methods 2.1. Animals and drugs Male Wistar rats Ž300–400g. were purchased from Japan SLC ŽShizuoka, Japan.. Animals were housed in a temperature- Ž22–24 8C., humidity- Ž55 " 5%. and lightŽ12 h light–dark cycle; lights on at 07:00.-regulated room with food and water ad libitum for at least 3 days before the experiments. The procedures involving animals and their care were conducted in accordance with AGuiding Principles for the Care and Use of Laboratory AnimalsB of Nagoya University, Japan. hADM, hPAMP, hADM-Ž1– 25., hADM-Ž22–52., hCGRP were purchased from Peptide Institute ŽOsaka, Japan.. All other chemical were obtained commercially and used without further purification. Peptides were dissolved in Ca2q- and Mg 2q-free Tyrode’s solution containing 20-mM HEPES buffer. 2.2. Crude peritoneal mast cells preparation Under pentobarbital anesthesia, the peritoneal cavity of rat was washed with 10 ml of Ca2q- and Mg 2q-free Tyrode’s solution, containing 0.1% Žweightrvolume. bovine serum albumin ŽBSA. and 10 unitsrml sodium heparin. After gentle massage of the abdomen for 3 min, peritoneal exudate cells ŽPEC. in fluid were obtained. Collected PEC fluid was washed three times with Ca2qand Mg 2q-free Tyrode’s solution, containing 0.1% Žwrv. BSA and 10-unitsrml sodium heparin by centrifugation Ž1200 rpm, 4 8C, 10 min.. The pellets were then resuspended in ice-cold Ca2q-, Mg 2q-free Tyrode’s solution, containing 20 mM HEPES buffer at a concentration of 5 = 10 6 mast cellsrml.
an ice-cold bath and then centrifuged at 2500 rpm, 4 8C for 10 min, and the supernatant was then collected. To determine the effects of ADM-Ž22–52. on the histamine release induced by ADM, ADM-Ž22–52. Ž10y5 M. was added to PEC fluid just before adding ADM Ž10y5 M.. To determine the effects of extracellular Ca2q on the histamine release induced by the peptides, the desired concentrations of Ca2q were added immediately before the pre-incubation period, after which samples were incubated with ADM Ž10y5 M. or PAMP Ž10y6 M.. The concentrations of Ca2q were selected Ž0.5–2 mM. to inhibit peptide-induced histamine release, as has been described elsewhere w20,21x. To assess the effect of benzalkonium chloride, desired concentrations of benzalkonium chloride were added before the pre-incubation period, after which samples were incubated with ADM Ž10y5 M.. The concentrations of benzalkonium chloride Ž1–7 mM. were chosen to selectively inhibit the activity of G protein of the Gi type w20,22x. Collected supernatants were kept at y80 8C until analysis. In all experiments, the amount of lactate dehydrogenase ŽLDH. in the supernatants was determined before and after the incubation in order to verify cell viability. 2.4. Measurement of histamine release from peritoneal mast cells The amount of supernatant histamine was determined according to the method of May et al. w23x. The extracted histamine was determined by high performance liquid chromatography. The mobile phase was composed of 40% methanol in water containing 0.042-M acetate buffer, pH 4.0. The chromatography was performed on a YMC Packed Column A-302 ŽYamamura Chemical Laboratories, Kyoto, Japan.. The flow rate was 1 mlrmin and the fluorescence was monitored at 460 nm with excitation at 360 nm. Total histamine release was determined in intact PEC fluid after lysis by boiling for 5 min. Spontaneous histamine release was less than 7% throughout all experiments.
2.3. Cell incubation Test tubes, each containing 0.9 ml of the PEC fluid, were pre-incubated for 10 min at 37 8C. Following this, 0.1 ml of each peptide solution was added to the medium. In order to estimate the time-course effect of ADM, the fragments of ADM, CGRP and PAMP on histamine release, PEC fluid was incubated for different times Ž0.5–15 min. with 10y6 M of ADM. To determine the dose-dependent effect of ADM and PAMP on histamine release, PEC fluid was incubated for 10 min with different concentrations of peptide solution Ž10y8 to 10y5 M.. After finishing the experiments, all test tubes were immediately placed in
Fig. 1. Time-course effect of ADM Ž10y6 M. on histamine release from rat peritoneal mast cells. Each point represents the mean"S.D. of three independent experiments.
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Fig. 2. ŽA. Dose-dependent effects of ADM Ž`., PAMP Žv ., and CGRP Ž'. on histamine release from rat peritoneal mast cell. Each point represents the mean " S.D. of four to eight independent experiments. ŽB. Dose-dependent effects of ADM-Ž1–25. ŽI. and ADM-Ž22–52. ŽB. on histamine release from rat peritoneal mast cell. Each point represents the mean " S.D. of eight independent experiments.
2.5. Statistical analysis Data are expressed as mean " S.D. of the net percent of total histamine release. Statistical analyses were performed using StatView ŽAbacus Concept, Barkeley, CA, USA..
3. Results As shown in Fig. 1, ADM Ž10y6 M. stimulated histamine release from rat peritoneal mast cell very rapidly and had a maximal effect within 0.5 min. Based on this
result, we selected 10 min as an incubation period for subsequent experiments. PAMP-induced histamine release also reached maximum within 10 min Ždata not shown.. Both ADM and PAMP dose-dependently induced histamine release from rat peritoneal mast cells ŽFig. 2A.. At the highest concentration tested Ž10y5 M., histamine release induced by ADM and PAMP was 49.4 " 3.2% and 47.0 " 7.0%, respectively. It should be noted that LDH release into the supernatants from mast cells treated with ADM Ž10y5 M. and PAMP Ž10y5 M. was less than 8% above background, which was not significantly different from control Ždata not shown., indicating that ADM in-
Fig. 3. ŽA. Effects of extracellular Ca2q on histamine release from rat peritoneal mast cells induced by ADM Ž10y6 M, `. and PAMP Ž10y5 M, v .. Each point represents the mean " S.D. of four and eight independent experiments, respectively. ŽB. Effects of benzalkonium chloride on histamine release from rat peritoneal mast cells induced by ADM Ž10y6 M, `.. Each point represents the mean " S.D. of four independent experiments, a p - 0.01 vs. ADM Ž10y6 M. ŽScheffe’s post-hoc test, followed by one-way ANOVA..
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duced histamine release was not associated with cytotoxicity. In contrast, CGRP, at concentrations up to 10y5 M, did not increase histamine release ŽFig. 2A.. ADM-Ž1–25. showed almost the same ability to induce histamine release as did full-length ADM, whereas, ADMŽ22–52. had no effect ŽFig. 2B.. At the highest concentration tested Ž10y5 M., histamine release induced by ADMŽ1–25. and ADM-Ž22–52. amounted to 53.7 " 4.0% and 12.4 " 4.3%, respectively. ADM Ž10y5 M.-induced histamine release was significantly inhibited by ADM-Ž22–52. Ž10y5 M. w71 " 7.2% of ADM Ž10y5 M.-induced histamine release, p - 0.05, data not shownx. As shown in Fig. 3A, addition of Ca2q into the assay buffer dose-dependently inhibited the histamine release induced by ADM Ž10y5 M. at a concentration of 0.5 mM or higher. In contrast, the highest extracellular calcium concentration tested Ž2 mM. failed to inhibit PAMP Ž10y5 M.-induced histamine release. Histamine release induced by ADM Ž10y6 M. and PAMP Ž10y5 M. in the presence of Ca2q Ž2 mM. was 2.4 " 0.6% and 49.0 " 2.6%, respectively. Fig. 3B shows the effects of benzalkonium chloride on histamine release from rat peritoneal mast cells. Indeed, benzalkonium chloride dose-dependently inhibited the histamine release induced by ADM Ž10y6 M..
4. Discussion In the present study, ADM and PAMP dose-dependently induced histamine release from rat peritoneal mast cells. The potency of ADM and PAMP in this regard is similar to that of other endogenous peptides, such as nociceptin w21x, midkine w20x, pituitary adenylate cyclase activating peptide ŽPACAP. w24x, substance P w25–27x, tachykinins w28x and neuropeptide Y w29x. The effect of ADM-Ž1–25. was similar to ADM, whereas, ADM-Ž22– 52. and CGRP failed to induce histamine release. ADMinduced histamine release was inhibited by ADM-Ž22–52., extracellular Ca2q and benzalkonium chloride, a selective inhibitor of G protein of the Gi type w20,22x. Similar to ADM, PAMP also induced histamine release from mast cells, although the effect of PAMP was insensitive to Ca2q. Taken together, these results suggest that ADM and PAMP, via different mechanisms, might play an important role in immune response. It is likely that a fragment of ADM, namely ADM-Ž16– . 21 , might be important for the pharmacological effects of ADM w2,30x. This fragment forms a six-membered ring structure that is conserved in different species Že.g., human, pig, bovine, rat, mouse, dog. w30x. For example, like full-length ADM, ADM-Ž15–22. possesses vasodilator activity, whereas, ADM-Ž22–52. and ADM-Ž40–52. do not w30x. In the present study, ADM-Ž1–25. showed the same effect as full-length ADM on histamine release, whereas
ADM-Ž22–52. did not induce histamine release by itself. Moreover, induction of histamine release from rat peritoneal mast cells by ADM occurred rapidly and reached its maximum effect within 30 seconds after the challenge. This is in contrast to Ig-E-induced histamine release from mast cells, which takes several minutes to reach its peak response w32,33x. Taken together, these results suggest the involvement of a putative ADM receptor on mast cells that mediates the effect on histamine release. A similar six-membered ring structure is also conserved in the CGRP families ŽCGRP, ADM, amylin.. Thus, there is a possibility that ADM and CGRP induced histamine release via a putative CGRP receptor. Indeed, CGRP stimulates the release of histamine from bronchoalveolar lavage in human w34x and from pig dural mast cells w35x, but not pig peritoneal mast cells w35x. Very recently, several ADM receptors, as well as CGRP receptors, have been cloned w2,3x. For example, McLatchie et al. w36x have demonstrated that the pharmacological profile of the calcitonin receptor-like receptor ŽCRLR. is altered by its association with the receptor-activity modifying proteins ŽRAMPs., with CRLRrRAMP-1 acting as the CGRP receptor and CRLRrRAMP-2 as the ADM receptor. Accordingly, it is of interest to evaluate more precisely the pharmacological characterization of a putative ADM receptor on mast cells. In the current experiments, CGRP at concentrations up to 10y5 M, did not induce histamine release, and this is partially consistent with previous evidence from pig peritoneal mast cells w35x. Alternatively, it has been reported that ADM-Ž22–52. has an ability to antagonize the effect of ADM by blocking the ADM receptor w2,31x. Indeed, in our model, ADM-Ž22–52. inhibited ADM-induced histamine release. Taken together, it is likely that the ADM receptor, rather than the CGRP receptor, may play an important role in ADM-induced histamine release from rat peritoneal mast cells, although further studies, including species- and origin-differences, are necessary. It has been reported that inhibition of Gi protein activity, or addition of extracellular Ca2q, can inhibit histamine release from peritoneal mast cells induced by midkine w20x, substance P w26x and nociceptin w21x. Interestingly, ADMinduced histamine release was inhibited by the selective Gi protein inhibitor benzalkonium chloride w20,22x and extracellular Ca2q, suggesting that it is regulated by Ca2q- and Gi-protein-sensitive pathways. Thus far, three molecularly defined receptors for ADM have been identified; calcitonin receptor-like receptor w37x, L1 orphan receptor w38x, and RDC-1 receptor w39x. These ADM receptors are all coupled to G proteins of the Gs type and adenylyl cyclase, which presumably stimulates accumulation of cAMP w2,3x. Further studies are necessary to elucidate the underlying mechanisms that regulate ADM-induced histamine release, including the potential contribution of the Gs-adenylyl cyclase-cAMP pathway. It should be noted that some peptides, such as neuropeptide Y w40x, substance P w29x and pituitary adenylate
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activating polypeptide ŽPACAP. w24x, might stimulate the release of mediators from mast cells via non-receptor mediated mechanisms w33,41x. For example, Grundemar et al. w42x demonstrated that the rank order of potency of neuropeptide Y and its fragments, to stimulate histamine release from mast cell, did not correlate with any previously known or postulated affinity for neuropeptide Y receptors. Moreover, similar evidence was observed in PACAP-stimulated release of histamine w25x and serotonin w41x from rat peritoneal mast cells. Seeback et al. w41x demonstrated that PACAP-stimulated serotonin-release was sensitive to either the phospholipase C inhibitors U73122 and D906, the protein kinase C inhibitor staurosporine, or the lipoxygenase inhibitor nordihydroxyguaiaretic acid, suggesting the involvement of multiple signaling pathways. It will, thus, be of interest to further elucidate whether or not ADM and PAMP act on their putative receptors to stimulate histamine release. The receptor for PAMP and PAMP-mediated cellular signaling has not been fully identified. Very recently, Ohinata et al. w43x demonstrated that PAMP shows affinity for bombesin receptor families in the nmol range in bombesin receptor-transfected BALB 3T3 cells. Interestingly, bombesin itself can induce histamine release from mast cells w44,45x. Accordingly, it is possible that PAMP is able to induce histamine release via a bombesin receptor. Further studies should be carried out to determine the underlying mechanism of action of PAMP. In conclusion, ADM and PAMP are capable of inducing histamine release from rat peritoneal mast cells. It is still uncertain whether the ADM-concentrations used ŽnM to mM range. in this study is physiologically relevant, since plasma levels of ADM are of the pM range w2x. Sensory neuronal terminals w2,35x and immune cells w17–19x, however, are good candidates for supplying ADM at the site of inflammation, and might elevate local ADM concentrations to a high level. Thus, ADM receptor antagonists acting on mast cells could inhibit the ADM-induced histamine release, potentially inhibiting inflammation.
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Acknowledgements We would like to thank Professor Tetsuo Hayakawa for his encouragement throughout this study.
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