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Biomedical subjects

Ellen C Ebert

Publications and source records attributed to Ellen C Ebert.

9 recordsLinked to original sources
PubMed2006

Human intestinal intraepithelial lymphocytes keep TNF alpha levels low by cell uptake and feedback inhibition of transcription.

BACKGROUND: Human intestinal intraepithelial lymphocytes (IELs) are mainly TCRalphabeta(+)CD8(+) T cells, juxtaposed between epithelial cells. Their release of TNFalpha, a cytokine that is toxic to the epithelium, is likely to be tightly regulated. This study documents a novel mechanism to keep TNFalpha levels low with stimuli that cause large fluctuations in IFNgamma release. METHODS: IELs were stimulated with combinations of IL-2, IL-12, and IL-15, without TCR ligation. TNFalpha and IFNgamma production was assessed at both the mRNA and protein levels. Uptake of both cytokines was analyzed by radioligand binding. RESULTS: By 72h with IL-15, IFNgamma concentrations increased markedly, while TNFalpha remained low. With IL-12 supplementation, IFNgamma increased 10-fold, while TNFalpha remained low. Initially, IELs had similar amounts of transcripts for IFNgamma and TNFalpha, indicating equivalent synthetic rates. Two events explain the low extracellular accumulation of TNFalpha. First, IELs took up 25-30% of bound (125)I-TNFalpha without undergoing apoptosis. In contrast, they incorporated little IFNgamma. Second, TNFalpha was under strict feedback control as shown by the reduction in transcription with the addition of TNFalpha. No feedback control was seen with IFNgamma. CONCLUSIONS: Extracellular TNFalpha, but not IFNgamma, levels are kept low by uptake of free cytokine followed by a decline in transcription, thereby avoiding accumulation of this potentially toxic cytokine.

Cells, Cultured↗
PubMed2006

Endogenous inhibitory cytokines repress TNFalpha secretion.

Tumor necrosis factor alpha (TNFalpha), with the potential to destroy tissue, is likely to be tightly regulated. A major regulatory step is the translational repression of TNFalpha. This study evaluates whether endogenous inhibitory cytokines account for this repression. Two cell populations were isolated from peripheral blood using techniques that minimized activation, one composed primarily of monocytes and the other containing T-cells and NK-cells. When cultured without a stimulus in the presence of Abs neutralizing IL-4, IL-10, or TGFbeta, each population released large amounts of TNFalpha, reaching levels induced by PHA or LPS. Their actions were at the post-translational level since the numbers of transcripts did not change, and inhibitors of protein or RNA synthesis had no effects. When inhibitors of 38 MAP kinase and ERK were added, T-cell release of TNFalpha proved to involve both pathways while monocytes were dependent on p38 but not ERK. Changes in soluble TNF receptor levels or cell uptake of TNFalpha were not involved. This study shows that low TNFalpha secretion by resting T-cells and monocytes is maintained by endogenous inhibitors that suppress post-translational processing of TNFalpha by MAP kinases. Keeping TNFalpha levels low is critical to the non-inflammatory steady-state.

Cytokines↗
PubMed2006

Esophageal disease in scleroderma.

Progressive systemic sclerosis (PSS) causes smooth muscle atrophy and fibrosis of the distal two-thirds of the esophagus. Motility studies show reduced-amplitude or absent peristaltic contractions in this region and normal or decreased lower esophageal sphincter pressure. Patients complain of dysphagia, heartburn, and regurgitation due to reflux and dysmotility. Complications include strictures found in 17% to 29% of patients and Barrett esophagus is 0% to 37%. Candida esophagitis is a complication of PSS not seen with non-PSS reflux. Esophageal disease correlates with pulmonary involvement but not with disease in the stomach or intestines. Whether reflux contributes to the pulmonary disease is an open question. Although manometry is the gold standard for diagnosis, cine-esophagram and scintography are only slightly less sensitive and should be considered for following the patients. Symptoms correlate poorly with evidence of esophagitis or abnormal 24-hour pH recordings. As a result, it is unclear which patients should receive acid-reducing or prokinetic medications and which medication to use. Aspiration precautions are important in those with severe esophageal dysmotility. This review of the literature highlights many areas of uncertainty in the diagnosis and treatment of esophageal disease in PSS that can be addressed in clinical studies.

Autonomic Nervous System↗
PubMed2006

CD2 activation of human lamina propria lymphocytes reduces CD3 responsiveness.

Lamina propria lymphocytes (LPLs) are thought to be antigen-activated memory T cells. Yet, they respond better to ligation of the CD2 receptor than the CD3 receptor by mitogenic antibodies. This study defines their constitutive state of activation and relates it to their CD3 hyporesponsiveness. The activated state of LPLs was demonstrated by their heightened display of the activated CD2 epitope, T11(3). Constitutive CD2 activation was shown by the reduction in spontaneous proliferation when the CD2-CD58 interaction was blocked. LPLs preferentially recognized CD58 rather than the major histocompatibility complex molecules on monocytes, triggering proliferation and interferon-gamma (IFN-gamma) secretion that was inhibited by blocking the CD2-CD58 interaction. To determine whether CD2 activation of LPLs contributes to their CD3 hyporesponsiveness, they were first stimulated with mitogenic CD2 antibodies and then tested for CD3-induced proliferation. The responses were greatly reduced by prior CD2 stimulation compared with LPLs cultured in medium alone. This effect was not caused by apoptosis or by changes in CD3 expression induced by CD2 triggering. This study shows that LPLs are constitutively activated through CD2, that they preferentially recognize CD58 on monocytes and that CD2 stimulation leads to CD3 hyporesponsiveness.

Antigen-Presenting Cells↗
PubMed2006

Hypoxic liver injury.

Hypoxic liver injury is defined as a massive, but transient, increase in serum transaminase levels due to an imbalance between hepatic oxygen supply and demand in the absence of other acute causes of liver damage. It typically occurs in elderly individuals with right-sided congestive heart failure and low cardiac output. Precipitating factors include arrhythmias or pulmonary edema. Symptoms include weakness, shortness of breath, and right upper quadrant pain. Less commonly, hypoxic liver injury is seen in patients with severe hypoxemia or septic shock. Characteristically, the transaminase level is elevated 20-fold but normalizes rapidly over several days. Imaging studies reveal hypoechoic or hypodense lesions that resolve completely with reversal of the initiating event. Treatment and prognosis depend on the underlyIng disease.

Cardiac Output↗
PubMed2005

IL-15 converts human intestinal intraepithelial lymphocytes to CD94 producers of IFN-gamma and IL-10, the latter promoting Fas ligand-mediated cytotoxicity.

Intestinal intraepithelial lymphocytes (IELs), T-cell receptor alphabeta(+) CD8(+) T cells located between epithelial cells, are thought to contribute to Fas ligand (FL)-mediated epithelial cell death in coeliac disease, a condition characterized by excess interleukin-15 (IL-15). This study evaluates the effects of prolonged IL-15 stimulation on IELs. Human IELs were obtained from jejunal mucosa from gastric bypass operations for morbid obesity and cultured for 3 or 10 days with IL-15. As the culture progressed, an increasing number of IELs became CD94(+) and produced massive quantities of interferon-gamma (IFN-gamma) and IL-10. There was a steady rate of transcription with no feedback regulation. Few chronically activated IELs produced IL-2, IL-4, or tumour necrosis factor-alpha (TauNuF-alpha). To determine whether the accumulation of IL-10 affected IEL functions, endogenous IL-10 was neutralized by antibody during culture with IL-15. This manipulation reduced expression of CD94, NKG2D, and FL as well as FL-mediated killing of Jurkat cells by IELs. It did not affect perforin or TNF-alpha expression or the associated cytotoxic activities. This study shows that IL-15 induces the development of CD94(+) IELs containing IFN-gamma and IL-10, and that endogenous IL-10 promotes FL-mediated cytotoxicity.

Antigens, CD↗
PubMed2004

Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease.

A major function of NKG2D linking innate and adaptive immunity is to upregulate antigen-specific CTL-mediated cytotoxicity in tissues expressing stress-induced NKG2D ligands, such as MIC, by coactivating TCR signaling. Here, we show that, under conditions of dysregulated IL15 expression in vivo in patients with celiac disease and in vitro in healthy individuals, multiple steps of the NKG2D/DAP10 signaling pathway leading to ERK and JNK activation are coordinately primed to activate direct cytolytic function independent of TCR specificity in effector CD8 T cells. These findings may not only explain previous reports of transformation of CTL into NK-like "lymphokine-activated killers" (LAK cells) under high doses of IL2 (a substitute for IL15) but may also have significant implications for understanding and treating immunopathological diseases.

Adolescent↗
PubMed2002

TCR specificity dictates CD94/NKG2A expression by human CTL.

Activating and inhibitory CD94/NKG2 receptors regulate CTL responses by altering TCR signaling, thus modifying antigen activation thresholds set during thymic selection. To determine whether their expression was linked to TCR specificity, we examined the TCR repertoire of oligoclonal CTL expansions found in human blood and tissues. High-resolution TCR repertoire analysis revealed that commitment to inhibitory NKG2A expression was a clonal attribute developmentally acquired after TCR expression and during antigen encounter, whereas actual surface expression depended on recent TCR engagement. Further, CTL clones expressing sequence-related TCR, and therefore sharing the same antigen specificity, invariably shared the same NKG2A commitment. These findings suggest that TCR antigenic specificity dictates NKG2A commitment, which critically regulates subsequent activation of CTL.

Amino Acid Sequence↗