Measles virus (MV) encodes the fusion protein (F) that mediates cell fusion and intercellular spread of the virus, and is homologous to the carboxy terminus of the neuropeptide substance P (SP). In addition, the oligopeptide Z-D-Phe-L-Phe-Gly, also homologous to F and SP, inhibits MV fusion with target cells. These observations raise the question of whether MV uses the SP receptor (SPR) during a specific phase of its infectious cycle. In this report, we examine the structural and functional consequences of this interaction and show, using cross-linking studies, that MV and SP specifically bind to a 52-58-kD protein, previously reported to comprise the SPR on human IM-9 lymphoblasts. Moreover, bound MV and SP are shown to reciprocally displace each other from these cells. In addition, we demonstrate that anti-SP antisera inhibits the cell-to-cell spread of MV, and that SP blocks MV fusion with target cells. These results indicate the presence of MV-SPR interactions during viral fusion, and suggest possible novel mechanisms for viral entry into cells.
G Harrowe, M Mitsuhashi, D G Payan
The spontaneously hypertensive rat (SHR) exhibits alterations in the renin-angiotensin-aldosterone system which are similar to those that characterize patients with "nonmodulating" hypertension, a common and highly heritable form of essential hypertension. Accordingly, we determined whether the inheritance of a DNA restriction fragment length polymorphism (RFLP) marking the renin gene of the SHR was associated with greater blood pressure than inheritance of a RFLP marking the renin gene of a normotensive control rat. In an F2 population derived from inbred SHR and inbred normotensive Lewis rats, we found the blood pressure in rats that inherited a single SHR renin allele to be significantly greater than that in rats that inherited only the Lewis renin allele. To the extent that the SHR provides a suitable model of "nonmodulating" hypertension, these findings raise the possibility that a structural alteration in the renin gene, or a closely linked gene, may be a pathogenetic determinant of increased blood pressure in one of the most common forms of essential hypertension in humans.
T W Kurtz, L Simonet, P M Kabra, S Wolfe, L Chan, B L Hjelle
C.B-17 scid mice were reconstituted by intraperitoneal injection of human tonsil cells or PBL from EBV-seronegative donors. Subsequent injection of EBV resulted in the rapid development (within 19-33 d) of aggressive, fatal, lymphoproliferative disorders of human B cell origin. Autopsies revealed solid tumors in the abdomen, and occasionally in the liver, thymus, or spleen. Histopathologic analysis showed that the tumors were high-grade immunoblastic lymphomas and FACS analyses of tumor cells indicated that they were of human B-lymphoid origin. The tumor cells grew in vitro and induced new tumors on injection into severe combined immunodeficient (SCID) mice. Karyotypic analysis and Southern blots for c-myc or bcl-2 rearrangements revealed no chromosomal abnormalities and translocations. Southern blot analysis also showed that the cells possessed EBV DNA sequences. Although these tumors undoubtedly reflect infection of the transferred B cells with EBV in vivo, intraperitoneal transfer of short-term lymphoid cell lines transformed in vitro with EBV resulted in ascites production without evidence of tumor formation.
M J Cannon, P Pisa, R I Fox, N R Cooper
G C Weir, S Bonner-Weir
W F Benedict, H J Xu, S X Hu, R Takahashi
To determine whether long-term hypertension leads to hyperplasia of myocyte nuclei in the heart, a phenomenon suspected to occur in humans, renal hypertension was produced in rats and the animals were killed 8 mo later. Arterial blood pressure remained elevated for approximately 5 mo, but decreased progressively in the last 3 mo so that at 8 mo this parameter was practically identical to that found in controls. Moreover, left ventricular end diastolic pressure was markedly increased in experimental animals in association with a substantial decrease in left ventricular dP/dt. The alteration of these physiological measurements was indicative of severe ventricular dysfunction. Quantitative analysis of the transmural distribution of myocyte nuclei in the left ventricle showed 36 and 23% increases in myocyte nuclei concentration in the epimyocardium and endomyocardium, respectively. These changes in nuclei were accompanied by 25 and 16% reductions in myocyte cell volume per nucleus in the outer and inner layers of the wall. In conclusion, long-term hypertension leads to impairment of ventricular function and proliferation of nuclei in myocytes.
P Anversa, T Palackal, E H Sonnenblick, G Olivetti, J M Capasso
Gastrin-releasing peptide (GRP), the 27 amino acid mammalian form of bombesin, was studied in human inferior turbinate nasal mucosa. The GRP content of the mucosa measured by radioimmunoassay was 0.60 +/- 0.25 pmol/g tissue (n = 9 patients; mean +/- SEM). GRP-immunoreactive nerves detected by the immunogold method of indirect immunohistochemistry were found predominantly in small muscular arteries, arterioles, venous sinusoids, and between submucosal gland acini. 125I-GRP binding sites determined by autoradiography were exclusively and specifically localized to nasal epithelium and submucosal glands. There was no binding to vessels. The effects of GRP on submucosal gland product release were studied in short-term explant culture. GRP (10 microM) significantly stimulated the release of the serous cell-specific product lactoferrin, and [3H]glucosamine-labeled glycoconjugates which are products of epithelial goblet cells and submucosal gland cells. These observations indicate that GRP released from nerve fibers probably acts on glandular GRP receptors to induce glycoconjugate release from submucosal glands and epithelium and lactoferrin release from serous cells, but that GRP would probably not affect vascular permeability.
J N Baraniuk, J D Lundgren, J Goff, D Peden, M Merida, J Shelhamer, M Kaliner
A H Beggs, L M Kunkel
Pooled normal polyspecific IgG for therapeutic use (IVIg) contain anti-idiotypes against idiotypic determinants expressed by autoantibodies from patients with a variety of autoimmune diseases. In the present study, antiidiotypes in IVIg are shown to recognize a cross-reactive idiotype on human anti-thyroglobulin (TG) autoantibodies, that was defined by heterologous antiidiotypic antibodies, termed anti-T44 antibodies. The T44 idiotype is located outside the antibody-combining site of anti-TG autoantibodies. F(ab')2 fragments from anti-T44 antibodies inhibited the binding of IVIg to affinity-purified F(ab')2 anti-TG autoantibodies. Anti-T44 antibodies bound to F(ab')2 fragments of patients' antibodies, which were retained on an affinity column of Sepharose-bound F(ab')2 fragments from IVIg, but not to F(ab')2 fragments from the effluent of the column. The T44 idiotype was expressed on antibodies that bound to IVIg from eight of nine patients with autoimmune thyroiditis, but not on IVIg-binding Igs from healthy individuals. A small amount of the T44 idiotype was also expressed on the fraction of IVIg that bound to itself upon affinity chromatography. The T44 idiotype was cross-reactive between antibodies from patients with autoimmune thyroiditis. Thus, IVIg contain antiidiotypic antibodies directed against an immunodominant disease-associated cross-reactive alpha-idiotype of human anti-TG autoantibodies. These results support the concept that IVIg may be beneficial in selected autoimmune diseases by modulating the function of the idiotypic network.
G Dietrich, M D Kazatchkine
The effect of PTH on chondrocyte proliferation as a function of cartilage age was examined. PTH[1-34] induced a 12- to 15-fold increase in the efficiency of colony formation in soft agar by chondrocytes from embryonic 13- to 19-d-old chickens and fetal 25-d-old rabbits with a 10-fold increase in their DNA content. It also caused a 2.5-fold increase in [3H]thymidine incorporation into DNA in fetal 25-d-old rabbit chondrocytes. No mitogenic responses to PTH were observed, however, in postnatal 7- to 21-d-old chick chondrocytes or postnatal 21-d-old rabbit chondrocytes. This age dependency was observed only with PTH: fibroblast growth factor, epidermal growth factor, and insulin stimulated chondrocyte proliferation irrespective of cartilage age. The absence of a mitogenic effect in postnatal chondrocytes was not due to a decrease in number or a reduction in affinity of receptors for PTH. PTH also increased [35S]sulfate incorporation into proteoglycans and the cyclic AMP level in fetal and postnatal chondrocytes, but at 100-fold higher concentrations (10(-8)-10(-7) M) than those (10(-10)-10(-9) M) required for the stimulation of cell division. These results suggest that PTH is a potent mitogen for embryonic chondrocytes, and that its mitogenic effect disappears selectively after birth.
T Koike, M Iwamoto, A Shimazu, K Nakashima, F Suzuki, Y Kato
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