LMP1 signaling and activation of NF-kappaB in LMP1 transgenic mice.

Transgenic mice expressing Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) under the control of an immunoglobulin heavy-chain promoter and enhancer develop lymphoma at a threefold higher incidence than LMP1-negative mice. In vitro, LMP1 activates numerous signaling pathways including p38, c-Jun N terminal kinase (JNK), phosphatidylinositol 3 kinase (PI3K)/Akt, and NF-kappaB through interactions with tumor necrosis receptor-associated factors (TRAFs). These pathways are frequently activated in EBV-associated malignancies, although their activation cannot be definitively linked to LMP1 expression in vivo. In this study, interactions between LMP1 and TRAFs and the activation of PI3K/Akt, JNK, p38, and NF-kappaB were examined in LMP1 transgenic mice. LMP1 co-immunoprecipitated with TRAFs 1, 2, and 3. Akt, JNK, and p38 were activated in LMP1-positive and -negative splenocytes as well as LMP1-positive and -negative lymphomas. Multiple forms of NF-kappaB were activated in healthy splenocytes from LMP1 transgenic mice, in contrast to healthy splenocytes from LMP1-negative mice. However, in both LMP1-positive and -negative lymphomas, only the oncogenic NF-kappaB c-Rel, was specifically activated. Similarly to EBV-associated malignancies, p53 protein was detected at high levels in the transgenic lymphomas, although mutations were not detected in the p53 gene. These data indicate that NF-kappaB is activated in LMP1-positive healthy splenocytes; however, NF-kappaB c-Rel is specifically activated in both the transgenic lymphomas and in the rare lymphomas that develop in negative mice. The LMP1-mediated activation of NF-kappaB may contribute to the specific activation of c-Rel and lead to the increased development of lymphoma in the LMP1 transgenic mice.

Mimicry of CD40 signals by Epstein-Barr virus LMP1 in B lymphocyte responses.

The effect of the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) on the activation and differentiation of normal B cells was investigated. B cells of transgenic mice expressing LMP1 under the control of immunoglobulin promoter/enhancer displayed enhanced expression of activation antigens and spontaneously proliferated and produced antibody. Humoral immune responses of LMP1 transgenic mice in CD40-deficient or normal backgrounds revealed that LMP1 mimics CD40 signals to induce extrafollicular B cell differentiation but, unlike CD40, blocks germinal center formation. Thus, these specific properties of LMP1 may determine the site of primary B cell infection and the state of infection in the natural course of EBV infection, whereas subsequent loss of LMP1 expression may affect the site of persistent latent infection.

Expression of the Epstein-Barr virus latent membrane protein 1 induces B cell lymphoma in transgenic mice.

The latent membrane protein 1 (LMP1) of the Epstein-Barr virus has transforming properties in rodent fibroblasts and is expressed in most of the cancers associated with Epstein-Barr virus (EBV) infection including posttransplant lymphomas, Hodgkin's disease, nasopharyngeal carcinoma, and AIDS-related lymphomas. In this study, three lineages of LMP1 transgenic mice were established with LMP1 expressed under the control of the Ig heavy chain promoter and enhancer. Lymphoma developed in all three lineages, and the incidence of lymphoma increased significantly with age with lymphomas developing in 42% of transgenic mice over 18 months. The expression of LMP1 was detected at high levels in the lymphoma tissues but only at trace levels in normal lymphoid tissues. Gene rearrangement of the Ig heavy chain indicated monoclonality or oligoclonality in all lymphomas, some of the lymphoid hyperplastic spleens, and some histologically normal spleens. These data reveal that LMP1, without the expression of other EBV genes, is oncogenic in vivo and indicate that LMP1 is a major contributing factor to the development of EBV-associated lymphomas.

Tetracycline-induced esophageal ulcer: a condition that probably more common than it appears to be.

Ten cases of tetracycline derivatives related drug induced esophageal ulceration were described. Five cases were due to minocycline and another five were due to doxycycline. Recumbent posture after drug ingestion was one of the predisposing factors. Odynophagia was the main symptom but may not be the presenting symptom. The diagnosis was easily confirmed by endoscopy. Single-contrast barium study was not sensitive for the demonstration of the esophageal ulcers. The recommended treatment includes cessation of the offending drug and symptomatic treatment. All recovered without any sequela within 3 to 11 days. The most important measure to prevent this condition is to instruct patients to take drugs in the upright position with at least 100 ml of water.

Medication-induced esophageal injury: report of 17 cases with endoscopic documentation.

We report on medication-induced esophageal injury (MIEI) in 17 patients (six male, 11 female) seen from October 1986 to May 1990. The mean age of patients was 27.3 (SD = 5.7) yr; mean duration of drug ingestion prior to the occurrence of symptoms 10.2 (SD = 11.5) days, and mean duration of symptoms before seeking medical attention 4.6 (SD = 3.8) days. Symptoms subsided after treatment, with a mean of 6 (SD = 2.5) days. Symptoms included odynophagia (in 17), chest pain (six), epigastric pain (three), and retrosternal pain (one). Symptoms occurred after the drug was stopped in three. MIEI was caused by doxycycline (seven), minocycline (five), Pantozyme (one), cloxacillin (one), unknown (two), and dicloxacillin + Danzen (one). Reclining after drug ingestion was the predominant risk factor. Endoscopy showed most ulcers to be multiple and at midesophagus. Barium swallows done in two patients were negative. There is no previous report of Pantozyme (pancreatic enzyme), Danzen (serratio-peptidase), cloxacillin, and dicloxacillin causing MIEI.