Evolution of interleukin-18 binding proteins and interleukin-1 receptor, type II proteins

Interleukin-18 (IL-18) is one of the pivotal cytokines controlling the defense mechanism called inflammation. As a first step to develop proteins for controlling the IL-18 level, we initiated a study of IL-18-binding proteins (IL-18BPs). Twenty-four IL-18BP family members, 11 from vertebrates and 13 from chordopoxviruses, were picked from the NCBI database. Eight of these vertebrate IL-18BPs and two of the chordopoxvirus IL18-BPs were identified here and characterized as new members of the IL-18BP family. Their IL-18 binding domains were aligned and the distribution of highly conserved critical amino acid residues was analyzed and used to construct a phylogenetic tree. From this tree it was inferred that at least two independent events created two different ancestral viral IL-18BP genes by retroposition of IL-18BP genes from the vertebrate lineage. These two events are estimated to have occurred after an ancient mammalian IL-18BP gene diverged from birds, and before the mammalian IL-18BP gene diverged into human, ungulate and rodent IL-18BP genes. Moreover, our results suggest that IL-18BP and interleukin-1 receptor, type II (IL-1R2) had a common ancestral gene and diverged from the ancestral gene into IL-18BP and IL-1R2 genes in the fish period.     

The role of tumor necrosis factor (TNF)-α in the antitumor effect of intrapleural injection of Lactobacillus casei strain Shirota in mice

The involvement of several cytokines in the antitumor effect induced by intrapleural (i.pl.) injection of heat-killed cells of Lactobacillus casei strain Shirota (LC 9018) in mice was investigated. Injection of LC 9018 i.pl. into Meth A fibrosarcoma (Meth A)-bearing mice not only significantly prolonged the survival of the mice, but also effectively inhibited the accumulation of malignant pleural fluid in the thoracic cavity. In the thoracic cavity of tumor-bearing mice treated with LC 9018, we observed large amounts of several cytokines including interleukin (IL)-1β, interferon (IFN)-γ, IL-12 and tumor necrosis factor (TNF)-α. Both anti-IFN-γ and anti-IL-12 monoclonal antibody (mAb) treatments partially diminished the antitumor activity of LC 9018 in vivo, while the treatment of anti-IL-1β mAb did not influence the survival of the mice. However, anti-TNF-α mAb treatment completely abolished the antitumor effect of LC 9018 in vivo, suggesting that in this model LC 9018 has a survival-prolonging effect involving certain cytokines. Moreover, i.pl. injection of mouse recombinant TNF-α into Meth A-bearing mice pretreated with anti-TNF-α mAb partially restored the survival-enhancing effect of LC 9018. These results led us to conclude that TNF-α induced by i.pl. injection of LC 9018 plays an important role in the antitumor effect of LC 9018 in vivo. Received: 22 February 1999     

The evolutionary origin of the major histocompatibility complex: Polymorphism of class II α chain genes in the cartilaginous fish

T cells recognize antigen (Ag) in the form of peptides bound to the major histocompatibility complex (MHC) molecule. One of the important issues in evolutionary immunology is to identify the stage in phylogeny when this mode of Ag recognition emerged. At present, there is a considerable controversy as to whether the cartilaginous fish have the bona fide MHC. In our previous study, we showed that the nurse shark, a member of the cartilaginous fish, has (a) gene(s) capable of encoding MHC class II a chains. In the present study, we examined the polymorphism of nurse shark MHC class II a chain genes designated Gici-DAA and Gici-DBA using the polymerase chain reaction. The Gici-DAA and Gici-DBA genes had six and five alleles, respectively, and individual alleles usually differed by multiple nucleotides. In addition, most of the nucleotide substitutions were located at the putative Ag-binding sites, where non-synonymous substitutions occurred more frequently than synonymous substitutions. The fact that the Gici-DAA and Gici-DBA genes display a polymorphism pattern essentially similar to that of mammalian MHC genes playing a major role in Ag presentation suggests that the cartilaginous fish have the bona fide MHC. Thus, the MHC-peptide-based T cell recognition system appears to have arisen at or before the emergence of the cartilaginous fish.     

The NK1 receptor and its participation in the synergistic enhancement of corneal epithelial migration by substance P and insulin-like growth factor-1

1. We have previously shown that substance P (SP) and insulin-like growth factor-1 (IGF-1) act synergistically to enhance the migration of rabbit corneal epithelial cells in an organ culture model. The present study was designed to identify the epithelial cell SP receptor that participates in this synergistic effect.
2. Rabbit corneal blocks were incubated for 24 h, then the length of the path of epithelial migration was measured. Reagents tried in the TC-199 culture medium, in the presence or absence of IGF-1, were: SP, agonists of tachykinin receptors NK₁, NK₂ or NK₃ and antagonists of tachykinin receptors NK₁ or NK₂.
3. The binding characteristics of SP receptors were examined in rabbit cultured corneal epithelial cells by binding assays with [¹²⁵I]-SP in the presence or absence of excess unlabelled SP or ligands of NK₁, NK₂ or NK₃ receptors.
4. As was demonstrated previously, SP and IGF-1 stimulated epithelial migration when they were added to the culture medium together, but individually they had no effect. NK₁ agonists had the same synergistic effect with IGF-1 as did SP, but the NK₂ and NK₃ agonists did not. Furthermore, the NK₁ antagonist abolished the synergistic effect of SP and IGF-1, but the NK₂ antagonist had no effect.
5. SP bound specifically to rabbit cultured corneal epithelial cells. The binding affinity was 0.44 nM and there were 2.43×10⁴ binding sites per cell. The NK₁ ligand competed, in a dose-dependent fashion, with the binding of SP to corneal epithelial cells, but neither the NK₂ nor NK₃ ligand affected binding.
6. We conclude that the SP receptor in rabbit corneal epithelial cells is NK₁ and that this receptor participates in the synergistic enhancement of corneal epithelial migration by SP and IGF-1. The precise mechanism(s) of this interaction requires more study. These findings imply that both neural and humoral factors are essential for the maintenance and healing of corneal epithelium.

     

Total Esophagectomy versus Proximal Esophagectomy for Esophageal Cancer at the Cervicothoracic Junction

To investigate the adequate extent of esophagectomy and lymphadenectomy for an esophageal cancer localized at the cervicothoracic junction, the mortality and morbidity rates, survival rates, and patterns of recurrence were retrospectively analyzed in two groups—14 patients who underwent total esophagectomy with or without laryngectomy and 15 patients who underwent proximal esophagectomy with or without laryngectomy—at Kurume University Hospital from 1981 to 1996. Proximal esophagectomy with or without laryngectomy resulted in a lower hospital mortality rate and better overall survival for patients who underwent curative esophagectomy compared with total esophagectomy with or without laryngectomy. Multivariate analysis indicated that the extent of esophagectomy (total esophagectomy versus proximal esophagectomy) was not a prognostic factor. The incidence of recurrence was not different between the two groups. Lymph node metastasis or recurrence from such esophageal cancers was localized to the neck and upper mediastinum. For an esophageal cancer localized at the cervicothoracic junction, therefore, proximal esophagectomy with or without laryngectomy and with cervical and upper mediastinal lymphadenectomy could be better indicated for preselected patients.     

Effects of prostacyclin analogue,OP-2507, on function and metabolism in the ischemic working rat heart

We examined the effects of a new stable prostacyclin analogue, OP-2507, on myocardial function and metabolism in the ischemic working rat heart preparation. The hearts were perfused with Krebs-Henseleit bicarbonate (KHB) buffer, and whole heart ischemia was induced by one-way aortic valve for 15min follows by reperfusion for 30min. In the treated hearts, OP-2507, 20ng·ml^–1, was administered to KHB buffer from the beginning to the end of experiment. During ischemia, coronary flow in the OP-2507 group increased significantly more than that in the control group. The mechanical performance of both groups was impaired after ischemia. However, the recovery of coronary flow, cardiac output, peak systolic pressure and LV dP/dT_max was significantly higher in the treated group than in the control group. The incidence of ventricular fibrillation during reperfusion was 100% and 25% in the control and the OP-2507 groups, respectively. Myocardial ATP content was significantly higher in the treated hearts than that in the control hearts. These results indicate that this stable prostacyclin analogue is beneficial in myocardial ischemia, even without its well known action of preventing platelet aggregation.(Oguchi T, Kashimoto S, Nakamura T, et al.: Effects of prostacyclin analogue, OP-2507, on function and metabolism in the ischemic working rat heart. J Anesth 6: 446–454, 1992)     

Therapeutic Potential of Monteplase in Acute Myocardial Infarction

Thrombolysis with conventional thrombolytic agents prior to percutaneous coronary intervention (PCI) has had no impact on the treatment of acute myocardial infarction (AMI). However, the development of mutant tissue type plasminogen activators (mt-PA) has prompted us to reassess the combination of thrombolysis and PCI. Monteplase is a newly developed mt-PA that can be administered as a single intravenous bolus injection. The results of the COMA (COmbining Monteplase with Angioplasty) trial, suggest that monteplase administration prior to emergent PCI in AMI improves 6-month outcomes and possibly the long-term prognosis of myocardial infarction. Combining monteplase administration on presentation at a community hospital with prompt transfer to a tertiary center for PCI would be an ideal strategy for the treatment of AMI.