Protein tyrosine phosphatase SAP-1 protects against colitis through regulation of CEACAM20 in the intestinal epithelium.

Intestinal epithelial cells contribute to regulation of intestinal immunity in mammals, but the detailed molecular mechanisms of such regulation have remained largely unknown. Stomach-cancer-associated protein tyrosine phosphatase 1 (SAP-1, also known as PTPRH) is a receptor-type protein tyrosine phosphatase that is localized specifically at microvilli of the brush border in gastrointestinal epithelial cells. Here we show that SAP-1 ablation in interleukin (IL)-10-deficient mice, a model of inflammatory bowel disease, resulted in a marked increase in the severity of colitis in association with up-regulation of mRNAs for various cytokines and chemokines in the colon. Tyrosine phosphorylation of carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 20, an intestinal microvillus-specific transmembrane protein of the Ig superfamily, was greatly increased in the intestinal epithelium of the SAP-1-deficient animals, suggesting that this protein is a substrate for SAP-1. Tyrosine phosphorylation of CEACAM20 by the protein tyrosine kinase c-Src and the consequent association of CEACAM20 with spleen tyrosine kinase (Syk) promoted the production of IL-8 in cultured cells through the activation of nuclear factor-κB (NF-κB). In addition, SAP-1 and CEACAM20 were found to form a complex through interaction of their ectodomains. SAP-1 and CEACAM20 thus constitute a regulatory system through which the intestinal epithelium contributes to intestinal immunity.

A Unique Case Involving a Female Patient with Upshaw-Schulman Syndrome: Low Titers of Antibodies against ADAMTS13 prior to Pregnancy Disappeared after Successful Delivery.

BACKGROUND: Upshaw-Schulman syndrome (USS) is usually suspected based on severe deficiency of ADAMTS13 activity without ADAMTS13 antibody, but the definitive diagnosis is made by ADAMTS13 gene analysis. We present a unique case of USS with low titers of ADAMTS13 antibodies before pregnancy. Interestingly, titers of ADAMTS13 antibodies decreased to almost undetectable levels after delivery. CASE REPORT: In patient LL4, the diagnosis of USS was confirmed at age 27 by ADAMTS13 gene analysis. She became pregnant at age 30. During the pregnancy, she received regular fresh frozen plasma (FFP) infusion. Plasma von Willebrand factor levels increase as pregnancy progresses. To prevent platelet thrombi, much more ADAMTS13 supplementation is necessary during late gestation in patients with USS. Therefore, we shortened the interval between and increased the volume of FFP infusions as pregnancy progressed. At 39 weeks, she delivered a healthy baby girl. Before pregnancy, she had low titers of both neutralizing and binding anti-ADAMTS13 antibodies. Despite frequent FFP infusions, titers of the antibodies did not increase, but rather decreased to almost undetectable levels during pregnancy. CONCLUSION: Both the neutralizing and binding antibodies against ADAMTS13 decreased to almost undetectable levels after delivery in this patient, which can be caused by an immunological reset.

Case of radioactive iodine exposure during pregnancy.

A 43-year-old woman (gravida 0, para 0) was diagnosed with thyroid carcinoma and had been receiving radioactive iodine for remnant ablation. Eventually, her pregnant status became apparent; during radiation, she was at 5 gestational weeks. She decided to continue the pregnancy and delivered a boy of 2362 g at 37 gestational weeks. The infant did not present thyroid dysfunction or developmental abnormalities at 2 months of age. The patient was in the early pregnancy stage during radiation, so the fetus did not develop radiation-related damage of the thyroid gland because at this stage, the fetal thyroid does not concentrate iodine. Although the mother had received radioactive iodine during the critical organogenesis period, the fetus did not develop teratogenicity because the radiation was administered at the borderline threshold for teratogenicity. This case suggests the importance of iodine thyroid absorption when considering radiation-related damage to the fetal thyroid gland during early pregnancy.

SAP-1 is a microvillus-specific protein tyrosine phosphatase that modulates intestinal tumorigenesis.

SAP-1 (PTPRH) is a receptor-type protein tyrosine phosphatase (RPTP) with a single catalytic domain in its cytoplasmic region and fibronectin type III-like domains in its extracellular region. The cellular localization and biological functions of this RPTP have remained unknown, however. We now show that mouse SAP-1 mRNA is largely restricted to the gastrointestinal tract and that SAP-1 protein localizes to the microvilli of the brush border in gastrointestinal epithelial cells. The expression of SAP-1 in mouse intestine is minimal during embryonic development but increases markedly after birth. SAP-1-deficient mice manifested no marked changes in morphology of the intestinal epithelium. In contrast, SAP-1 ablation inhibited tumorigenesis in mice with a heterozygous mutation of the adenomatous polyposis coli gene. These results thus suggest that SAP-1 is a microvillus-specific RPTP that regulates intestinal tumorigenesis.

Gram-negative bacterial lipopolysaccharide stimulates activin a secretion from human amniotic epithelial cells.

Activin A is involved in inflammation. The present study was performed to clarify if lipopolysaccharide, a component of Gram-negative bacteria, stimulates activin A secretion from human amniotic epithelial cells and to determine if activin A plays a role in amnionitis. Fetal membranes were obtained during elective cesarean sections performed in full-term pregnancies of patients without systemic disease, signs of premature delivery, or fetal complications. Amniotic epithelial cells were isolated by trypsinization. The activin A concentrations in the culture media were measured by enzyme-linked immunosorbent assay, and cell proliferation was assessed by 5-bromo-2'-deoxyuridine incorporation. Amniotic epithelial cells secreted activin A in a cell density-dependent manner, and lipopolysaccharide (10 µ g/mL) enhanced the secretion at each cell density. Lipopolysaccharide (10-50 µ g/mL) also stimulated activin A secretion in a dose-dependent manner. Contrary to the effect of activin A secretion, lipopolysaccharide inhibited cell proliferation in amniotic epithelial cells. The present study suggests that lipopolysaccharide stimulation of activin A secretion may be a mechanism in the pathogenesis of amnionitis.