Expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in acute and chronic inflammation.
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The objective of this study was to quantify, in vivo, constitutive and tumor necrosis factor alpha (TNF-alpha)-enhanced expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in different tissues from healthy wild-type mice (C57BL/6) as well as interleukin-10 (IL-10)-deficient mice with and without active colitis. Using the dual radiolabel monoclonal antibody technique, we found substantial constitutive expression of MAdCAM-1 in the intestine, colon, and mesenteric lymph nodes. MAdCAM-1 expression in these tissues was significantly enhanced, in a time-dependent manner, by systemic administration of TNF-alpha. Maximum surface expression was observed at 18 h after TNF-alpha administration and remained significantly elevated at 48 h post-TNF-alpha injection. No significant constitutive nor TNF-alpha-induced expression of MAdCAM-1 was detected in skeletal muscle, brain, or heart. In IL-10-deficient (IL-10 k/o) mice with no clinical or histological evidence of colitis, constitutive and TNF-alpha-induced expression of MAdCAM-1 in the intestine, cecum, and colon was not different from those values obtained with healthy wild-type controls. IL-10-deficient mice with active colitis exhibited a four- to fivefold greater expression of MAdCAM-1 in the cecum and colon compared with their healthy controls or to IL-10 k/o mice with no evidence of colitis. Taken together, these data demonstrate that TNF-alpha enhances surface expression of MAdCAM-1 in intestinal and colonic tissues to the same extent in both wild-type and IL-10 k/o mice with no colonic inflammation, whereas IL-10 k/o mice with active colitis exhibited a profound up-regulation of MAdCAM-1 in the colon. (+info)
Cloning of the gene gob-4, which is expressed in intestinal goblet cells in mice.
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We isolated the novel cDNA gob-4, which was shown to be expressed in intestinal goblet cells. The deduced amino acid sequence is similar to the gene coding for the Xenopus laevis cement gland-specific XAG-2. These sequence and expression data suggest this gene may be involved in the secretory function. (+info)
Binding of human neutrophils to cell-surface anchored Tamm-Horsfall glycoprotein in tubulointerstitial nephritis.
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BACKGROUND: Human Tamm-Horsfall glycoprotein (T-H) is a glycosylphosphatidylinositol-anchored protein exposed at the surface of distal nephron cells, and urinary T-H is the released soluble counterpart. The latter has been implicated in tubulointerstitial nephritis, and the proinflammatory potential has been related to its ability to bind in vitro human neutrophils (PMNs). We have examined the conditions required for the binding of neutrophils to cell-surface anchored T-H and the consequent effects. METHODS: A HeLa cell-line derivative permanently transformed with human T-H cDNA and expressing T-H at the cell surface was used throughout the study. The adhesion of PMNs to cells expressing T-H was analyzed by immunofluorescence microscopy before and after the opsonization of cells with anti-T-H antibodies. The oxidative burst induced by adhesion of PMNs to the cells was determined by the activation of myeloperoxidase. Quantitative and qualitative changes in the release of T-H under the adhesion of activated PMNs were determined by dot-blot and Western blot analysis. RESULTS: No binding of neutrophils to cell-surface-anchored T-H was observed. On the contrary, the opsonization of cells with anti-T-H antibodies resulted in a dramatic adhesion of neutrophils. Such an adhesion induced the oxidative burst of PMNs and a large increment in the release of T-H, as well as the release of the slightly faster migrating T-H form, which is normally retained intracellularly. CONCLUSIONS: These results support the notion that, after the autoimmune response, the adhesion of neutrophils to cell-surface T-H contributes to the pathogenesis of tubulointerstitial nephritis, favoring a further accumulation of T-H in the interstitium and inducing the loss of cell integrity via reactive oxygen metabolites generated by activated neutrophils. (+info)
Distribution of lymphocytes and adhesion molecules in human cervix and vagina.
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Knowledge of the histological distribution of leucocytes and adhesion molecules in the human genital tract is scarce although local immunity in this region is important. Using immunohistochemical methods, we here describe the organization of CD3+, CD8+ and CD4+ T cells, CD19+ B cells, CD38+ plasma cells, major histocompatibility complex (MHC) class II+ antigen-presenting cells and CD14+ monocytes, as well as the expression of endothelial addressins in normal human ecto-cervical and vaginal mucosa. T cells were clustered in a distinct band beneath the epithelium and were also dispersed in the epithelium and the lamina propria, whereas CD38+ plasma cells were present only in the lamina propria. MHC class II+ cells were numerous in the lamina propria and in the epithelium, where they morphologically resembled dendritic cells. Lymphoid aggregates containing CD19+ and CD20+ B cells as well as CD3+, CD4+ and CD8+ cells were also found in the cervix. The mucosal addressin cell adhesion molecule-1 (MAdCAM-1) was not expressed on the vascular endothelium in the cervical or vaginal mucosa. In contrast, intercellular adhesion molecule-1 (ICAM-1), vascular adhesion protein-1 (VAP-1) and P-selectin were expressed in all tissue samples, and vascular cell adhesion molecule-1 (VCAM-1) and E-selectin were found in four of seven samples. We conclude that the distribution of leucocytes and adhesion molecules is very similar in the ecto-cervical and the vaginal mucosa and that the regulation of lymphocyte homing to the genital tract is different from that seen in the intestine. Our results also clearly suggest that the leucocytes are not randomly scattered in the tissue but organized in a distinct pattern. (+info)
Selective antibody blockade of lymphocyte migration to mucosal sites and mast cell adhesion.
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The integrins alpha4beta7 and alpha4beta1 mediate adhesion to the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and the vascular cell adhesion molecule-1 (VCAM-1) and are important in T cell and allergic inflammatory reactions in the rat. The relative contributions of alpha4beta7 and alpha4beta1 in these reactions is unknown. To examine the role of alpha4beta7 in the rat a new mAb, TA-6, was developed. TA-6 inhibited adhesion to MAdCAM-1 but not to VCAM-1, a characteristic of alpha4beta7 adhesion, and immunofluorescence and immunoprecipitation studies were compatible with binding to alpha4beta7. TA-6 blocked rat lymphocyte adhesion to mesenteric lymph nodes and T cell migration to mucosal lymphoid tissues and it bound to rat mucosal mast cells. TA-6 did not inhibit lymphocyte adhesion to peripheral lymph nodes and T cell migration to peripheral lymphoid tissues or cutaneous inflammatory sites, and was not expressed on connective tissue mast cells. (+info)
Rapid evolution of fertilization selectivity and lysin cDNA sequences in teguline gastropods.
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Proteins mediating intercellular recognition face opposing selective forces as they evolve: purifying selection to maintain function, and diversifying selection to alter specificity. Lysin is a 16-kDa protein which enables sperm of free-spawning marine snails to make a hole in the vitelline layer (VE) surrounding conspecific eggs. Previous work on abalone (Haliotis spp.) has shown that positive selection promotes rapid interspecific divergence of lysin. Here, we present data on the specificity of VE dissolution by four species of teguline gastropods, along with lysin cDNA sequences. The teguline and abalone lineages diverged over 250 MYA. As in abalone, VE dissolution by lysin in tegulines is species-selective, and positive selection promotes rapid interspecific divergence over the entire mature protein. Nonsynonymous substitution rates, calculated using a mtCOI molecular clock calibrated by two Tegula species separated by the Isthmus of Panama, are high (> 25 substitutions per site per 10(9) years). However, the extensive replacements in teguline lysins are overwhelmingly conservative with respect to type, charge, and polarity of residues. Predictions of secondary structure suggest that the size and position of alpha-helices are also conserved, even through pairwise amino acid identities between Haliotis rufescens and the different tegulines are less than 15%. (+info)
Nasal-associated lymphoid tissue: phenotypic and functional evidence for the primary role of peripheral node addressin in naive lymphocyte adhesion to high endothelial venules in a mucosal site.
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Nasal-associated lymphoid tissue (NALT), a mucosal inductive site for the upper respiratory tract, is important for the development of mucosal immunity locally and distally to intranasally introduced Ag. To more fully understand the induction of nasal mucosal immunity, we investigated the addressins that allow for lymphocyte trafficking to this tissue. To investigate the addressins responsible for naive lymphocyte binding, immunofluorescent and immunoperoxidase staining of frozen NALT sections were performed using anti-mucosal addressin cell adhesion molecule-1 (MAdCAM-1), anti-peripheral node addressin (PNAd), and anti-VCAM-1 mAbs. All NALT high endothelial venules (HEV) expressed PNAd, either associated with MAdCAM-1 or alone, whereas NALT follicular dendritic cells expressed both MAdCAM-1 and VCAM-1. These expression profiles were distinct from those of the gut mucosal inductive site, Peyer's patches (PP). The functionality of NALT HEV was determined using a Stamper-Woodruff ex vivo assay. The anti-L-selectin MEL-14 mAb blocked >90% of naive lymphocyte binding to NALT HEV, whereas the anti-MAdCAM-1 mAb, which blocks almost all naive lymphocyte binding to PP, minimally blocked binding to NALT HEV. NALT lymphocytes exhibited a unique L-selectin expression profile, differing from both PP and peripheral lymph nodes. Finally, NALT HEV were found in increased amounts in the B cell zones, unlike PP HEV. These results suggest that NALT is distinct from the intestinal PP, that initial naive lymphocyte binding to NALT HEV involves predominantly L-selectin and PNAd rather than alpha4beta7-MAdCAM-1 interactions, and that MAdCAM-1 and VCAM-1 expressed by NALT follicular dendritic cells may play an important role in lymphocyte recruitment and retention. (+info)
Altered expression of Na transporters NHE-3, NaPi-II, Na-K-ATPase, BSC-1, and TSC in CRF rat kidneys.
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In chronic renal failure (CRF), reduction in renal mass leads to an increase in the filtration rates of the remaining nephrons and increased excretion of sodium per nephron. To address the mechanisms involved in the increased sodium excretion, we determined the total kidney levels and the densities per nephron of the major renal NaCl transporters in rats with experimental CRF. Two weeks after 5/6 nephrectomy (reducing the total number of nephrons to approximately 24 +/- 8%), the rats were azotemic and displayed increased Na excretion. Semiquantitative immunoblotting revealed significant reduction in the total kidney levels of the proximal tubule Na transporters NHE-3 (48% of control), NaPi-II (13%), and Na-K-ATPase (30%). However, the densities per nephron of NHE-3, NaPi-II, and Na-K-ATPase were not significantly altered in remnant kidneys, despite the extensive hypertrophy of remaining nephrons. Immunocytochemistry confirmed the reduction in NHE-3 and Na-K-ATPase labeling densities in the proximal tubule. In contrast, there was no significant reduction in the total kidney levels of the thick ascending limb and distal convoluted tubule NaCl transporters BSC-1 and TSC, respectively. This corresponded to a 3.6 and 2.5-fold increase in densities per nephron, respectively (confirmed by immunocytochemistry). In conclusion, in this rat CRF model: 1) increased fractional sodium excretion is associated with altered expression of proximal tubule Na transporter expression (NHE-3, NaPi-II, and Na-K-ATPase), consistent with glomerulotubular imbalance in the face of increased single-nephron glomerular filtration rate; and 2) compensatory increases in BSC-1 and TSC expression per nephron occur in distal segments. (+info)