Biomedical subjects
Publications and source records attributed to V Mutt.
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Vasoactive intestinal peptide, at different concentrations, was tested on the migration of leucocytes by using the sealed capillary migration test. Vasoactive intestinal peptide, at 10(-7)-10(-9)M, inhibited, while at 10(-12)-10(-14)M, stimulated mononuclear leucocyte migration. The migration of polymorphonuclear leucocytes was inhibited by vasoactive intestinal peptide at 10(-6)-10(-9)M, a stimulation was found at 10(-13)-10(-14)M. The inhibiting effect of vasoactive intestinal peptide on leucocyte migration was abolished when vasoactive intestinal peptide was split into C- and N-terminal fragments, while a stimulating effect was retained in the N-terminal fragment, at 10(-14)M, for mononuclear cells. Helodermin and peptide T, as well as two other members of the secretin-glucagon family, secretin and gastric inhibitory peptide, had no effect on the migration. When VIP antiserum was tested, it had an inhibiting effect, which was not seen with control serum, supporting a physiological effect of the lower vasoactive intestinal peptide concentrations. Vasoactive intestinal peptide seems to have dual effects on mononuclear and polymorphonuclear leucocyte migration and, generally, intact vasoactive intestinal peptide seems to be needed for these effects.
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A 28-residue N-terminal fragment of triosephosphate isomerase, TIM(1-28), has been purified from porcine upper intestine. It competes with VIP for binding to the VIP receptor on rat liver plasma membranes with an IC50 value of 2.8 mM, about 1000 times higher than that for VIP binding to the membranes. Except for a single positional identity and the number of amino acid residues, the amino acid sequences of TIM(1-28) and VIP are unrelated as regards primary structure. However, the ability to bind to the same receptor site may indicate common three-dimensional structural properties.
Intracerebroventricular injections (140-4300 pmol) of a 60-residue polypeptide (now designated PEC-60) isolated from pig intestine produced a dose-dependent increase (peak action 21% +/- 2; ED50 value of 1.7 nmol for the peak effect) in mean arterial blood pressure (MAP) in the awake, unrestrained male rat. The heart rate (HR) was significantly reduced with the highest doses used (1400 and 4300 pmol). The pancreatic secretory trypsin inhibitor (PSTI), with a high degree of sequence similarity to PEC-60, did not significantly change MAP and HR (4300 pmol). These results may indicate a biological role for the putative PEC-60-like peptide demonstrated within central catecholamine cardiovascular neurons.
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A precursor to the gastrointestinal hormone secretin has been isolated. The starting material for the purification of the precursor was a peptide fraction purified from pig intestinal extracts, containing peptides with a molecular weight higher than that of secretin. The purification could be followed by measurement of secretin bioactivity (alkali secreted in the pancreatic juice of anesthetized cat). Sequence analysis of the isolated secretin precursor revealed a 71-amino acid residue polypeptide that contained the sequence of secretin N terminally, followed by a Gly-Lys-Arg sequence and a C-terminal extension of 41-amino acid residues. With the exception of an arginine residue, which occurs directly after the Gly-Lys-Arg sequence, the remainder of the C-terminal residues in this precursor are identical to the 40 C-terminal residues predicted by the recently described cDNA sequence for porcine preprosecretin. Compared to the deduced preprosecretin sequence, a stretch of 32 amino acid residues directly following the Gly-Lys-Arg sequence is missing in the now purified secretin precursor. This implies that differential splicing may occur when the secretin gene transcript is processed to mRNA.
Work carried out in different laboratories has shown that the peptide pattern of the intestinal tissue is very complex and that some of the peptides are identical to those found in the central nervous system. The best studied of the peptides are of a hormonal nature, but recently evidence has been obtained that others may primarily act as antibiotics. In addition, peptides have been isolated that are fragments of some well-known proteins that have not been viewed as being prohormones. Whether the latter peptides only represent transient degradation products of the proteins or whether, at least some of them, have a physiologically meaningful selective function of their own is not yet clear.
Mammalian forms of neuropeptide Y (NPY) for which the amino acid sequences have previously been determined, are the human, pig, ox, rabbit, rat, and guinea-pig polypeptides. The only difference among these forms is at position 17, where pig and ox NPY have Leu and the others Met. We now show that sheep NPY differs from all the earlier characterized mammalian forms of NPY by having Asp instead of Glu at position 10. At position 17 it has Leu as do both pig and ox NPY. Consequently, 3 different structural types of mammalian NPY are now known.
The effects of natural peptide YY on pancreatic secretion under different stimulatory conditions and on fatty acid-induced cholecystokinin release were examined in five conscious dogs with pancreatic and gastric fistulas. Intravenous infusion of natural peptide YY at 1 and 0.2 microgram/kg/hr caused 60 and 40% inhibition of secretin- and cholecystokinin-stimulated secretion, respectively, and 40-50 and 20-40% inhibition of intraduodenal oleate stimulated secretion, respectively. A significant but transient decrease in the plasma cholecystokinin level was observed in response to peptide YY under oleate stimulation. The present study demonstrates that peptide YY has a potent inhibitory effect on both exogenously and endogenously stimulated pancreatic secretion and has a mild suppressive effect on fatty acid-induced cholecystokinin release suggesting that this peptide is an important colonic inhibitor of pancreatic secretion.
We have isolated from pig intestine a 60-residue polypeptide initially identified by its inhibition of glucose-induced insulin secretion from perfused pancreas. The amino acid sequence of this porcine polypeptide was determined and found to be markedly similar to that of the pancreatic secretory trypsin inhibitor (41% residue identities). Furthermore, the disulfide arrangements of these two proteins appear identical, suggesting related overall conformations. However, the polypeptide, now named PEC-60 (peptide with N-terminal glutamic acid, C-terminal cysteine, and a total of 60 residues), was found not to inhibit trypsin. The amino acid sequence is also similar to that of a peptide recently isolated from rat bile/pancreatic juice which stimulates the release of cholecystokinin. The biological role of PEC-60 is not known, but the effect on insulin secretion and the homologies observed suggest important biological activities and interesting structural relationships.
Pig small intestine was used as starting material for a batchwise isolation of a peptide fraction enriched in antibacterial activities against Escherichia coli (anti-Ec factor) and against Bacillus megaterium (anti-Bm factor). Separation and further purification were by different types of chromatography. Sequence analysis showed the anti-Bm factor to be apparently similar to vasoactive intestinal peptide. The anti-Ec factor was found to have a 31-residue sequence that was cecropin-like. It was named cecropin P1 and its structure was confirmed by solid-phase synthesis. Synthetic cecropin P1 with and without C-terminal amide was assayed on eight different bacteria. Mobility comparison between synthetic and natural cecropin P1 indicates that the natural peptide has a free C-terminal carboxyl group.
Among 30 patients with islet cell neoplasms or hyperplasia who exhibited marked gastric acid hypersecretion and peptic ulceration and/or diarrhea, fasting plasma gastrin concentrations were less than 150 pg/ml in 11 patients, whereas the remaining 19 patients had hypergastrinemia. Plasma extracts from seven of these 11 patients were assayed for acid secretagogue activity in rats. All seven plasma extracts had secretagogue activity that was not found in the plasma extracts of ten patients with ordinary duodenal ulcer disease. Each of the tumor or pancreatic tissue extracts obtained from nine patients exhibited secretagogue activity in rats even though tissue gastrin content was 101.9 pmol (213.8 ng).g-1 or less. The secretagogue activity of the tumor extracts was confirmed in conscious gastric fistula dogs. The tumors' secretagogue activity, in contrast to gastrin, was destroyed by trypsin. It was eluted between porcine motilin and human gastrin I from a Sephadex G-50 (Pharmacia LKB Biotechnology, Inc., Piscataway, NJ) superfine column and was not retained by CM-cellulose, at pH 8.5. Its retention time during reverse phase HPLC on a C18 column also differed from those of G17 and G34. Thus, this secretagogue activity appeared mediated by a small, acidic peptide with a molecular size of about 2000 to 3000 daltons. The present study indicates that plasma and tumor extracts of these 11 patients contain a gastric acid secretagogue activity mediated by a nongastrin peptide. We suggest that what may be a distinct clinical entity associated with endocrine neoplasms of the pancreas should be considered in the face of excessive acid hypersecretion without fasting hypergastrinemia.
Neuropeptides and monoamines are found in tissues where immune reactions are initiated such as the skin, gut and respiratory tract. In these tissues they might influence lymphocyte activation in inflammatory diseases. Both stimulatory and inhibitory effects have been described. The inhibitory effects may prove to be of pathophysiological and pharmacological importance. Studies both in vitro and in vivo showing that various neuropeptides and monoamines may inhibit reactions such as T lymphocyte proliferation, Blymphocyte proliferation and antibody synthesis, lymphocyte migration and cytotoxicity, are reviewed.
The polypeptide DBI (diazepam-binding inhibitor) has been purified from the porcine upper intestine, where it is abundant. Porcine mature DBI is composed of 86 amino acid residues and has a blocked N-terminus. The primary structure, the first DBI structure determined at the protein level, differs from those indirectly deduced for human and rat DBI at 11 and 17 positions, respectively. In total, the three mammalian DBIs differ at 22 positions but have exactly identical C-terminal 11-residue segments, highly charged and ending with C-terminal isoleucine. The porcine DBI inhibits both the early and the late phase of glucose-induced insulin release from the isolated perfused rat pancreas. Thus, the results identify by direct analysis the presence of DBI at a non-cerebral localization (gut), establish a novel structural form (porcine) and demonstrate a novel bioactivity (on insulin release). These aspects are of special interest in relation to the conserved segments, including the one at the C-terminal end, which may constitute functionally important parts of the polypeptide. It is possible that DBI belongs to a new family of gut polypeptides which inhibit glucose-mediated insulin release by hormonal and/or neurocrine mechanisms.
Neuropeptides and monoamines have been found in tissues where immune reactions are initiated such as the skin, gut, and respiratory tract, and in these tissues neuropeptides and monoamines might be involved in the regulation of lymphocyte activation. Studies both in in vitro and in vivo showing that various neuropeptides and monoamines may influence reactions such as T lymphocyte proliferation, B lymphocyte proliferation, and antibody synthesis, lymphocyte migration, and cytotoxicity will be reviewed.
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