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Biomedical subjects

H Kendall

Publications and source records attributed to H Kendall.

9 recordsLinked to original sources
PubMed2001

The 3' untranslated region of tumor necrosis factor-alpha is highly conserved in idiopathic pulmonary fibrosis (IPF).

Tumour necrosis factor alpha (TNF-alpha), a pro-inflammatory cytokine essential for the function of the immune system, has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Production of TNF-alpha is regulated at both the transcriptional and post-transcriptional levels by a number of factors including interleukin-10 (IL-10). We have shown that there is significant TNF-alpha activity in patients with IPF, despite the presence of significant amounts of IL-10 and Il-10R. IL-10 is thought to influence the tight translational repression of TNF-alpha mRNA in pulmonary macrophages. The essential element in this regulation is the AU-rich element (ARE) present in the 3' untranslated region of TNF-alpha. We hypothesised that polymorphism in the 3' UTR region of TNF-alpha explains the apparent failure of IL-10 to down regulate TNF-alpha in patients with IPF. Using single strand conformation polymorphism (SSCP) analysis, we have screened this region in 96 patients with IPF, using nine sets of overlapping PCR primers. All samples were successfully amplified for each primer set, but SSCP analysis was unable to detect point mutations or polymorphisms in the patients in any of the nine fragments. Results from this study suggest that the 3' UTR region of TNF-alpha is highly conserved in IPF and mutation of this region is unlikely to be involved in the pathogenesis of IPF.

3' Untranslated Regions↗
PubMed2000

Increased expression of functionally active membrane-associated tumor necrosis factor in acute respiratory distress syndrome.

Membrane-associated tumor necrosis factor (mTNF) has recently been shown to induce inflammatory cellular responses previously attributed to the soluble form. The present study measures for the first time the expression and function of mTNF on the surface of alveolar macrophages (AMs) to determine whether it is associated with the development of acute respiratory distress syndrome (ARDS). TNF expression was determined by flow cytometry, and the function of mTNF on the surface of AMs was determined by an in vitro cytotoxicity assay. Tumor necrosis factor (TNF)-alpha bioactivity was measured by bioassay. Soluble TNF receptor (TNFR) protein and messenger RNA (mRNA) expression were measured by enzyme-linked immunosorbent assay and reverse transcriptase/polymerase chain reaction, respectively. Increased detection of mTNF was observed on the surface of AMs derived from subjects with ARDS (mean percentage increase in fluorescence 22.30 +/- 3.50% for subjects with ARDS compared with 7.09 +/- 1.70% for At Risk subjects [P < 0.003]). mTNF cytotoxicity in the bioassay positively correlated with the mTNF expression determined by flow cytometry (r(2) = 0.97). Although there was increased mTNF expression and cytotoxic function in ARDS, there was no significant increase in soluble TNF expression in the bronchoalveolar lavage fluid or the AM supernatants. Lower levels of CD120b-soluble TNFR were detected in the AM supernatants derived from subjects with ARDS compared with At Risk (mean 0.264 +/- 0.058 versus 0.593 +/- 0.143 ng/ml, respectively [P < 0.05]). By contrast, there was increased CD120b mRNA expression in AMs derived from subjects with ARDS (P < 0.03), suggesting that increased surface expression of this receptor may be important in mediating the signal of mTNF. These data demonstrate for the first time the presence of functionally active mTNF on the surface of AMs in ARDS and highlight a potential mechanism for TNF-mediated lung injury.

Acute Disease↗
PubMed1993

Antagonism of catecholamine receptor signaling by expression of cytoplasmic domains of the receptors.

The actions of many hormones and neurotransmitters are mediated by the members of a superfamily of receptors coupled to heterotrimeric guanine nucleotide-binding proteins (G proteins). These receptors are characterized by a highly conserved topographical arrangement in which seven transmembrane domains are connected by intracellular and extracellular loops. The interaction between these receptors and G proteins is mediated in large part by the third intracellular loop of the receptor. Coexpression of the third intracellular loop of the alpha 1B-adrenergic receptor with its parent receptor inhibited receptor-mediated activation of phospholipase C. The inhibition extended to the closely related alpha 1C-adrenergic receptor subtype, but not the phospholipase C-coupled M1 muscarinic acetylcholine receptor nor the adenylate cyclase-coupled D1A dopamine receptor. These results suggest that the receptor-G protein interface may represent a target for receptor antagonist drugs.

Amino Acid Sequence↗