Biomedical subjects

G Gehr

Publications and source records attributed to G Gehr.

4 recordsLinked to original sources

PubMed1993

Tumor necrosis factor alpha (TNF-alpha)-induced cell adhesion to human endothelial cells is under dominant control of one TNF receptor type, TNF-R55.

Tumor necrosis factor alpha (TNF-alpha) is a pleiotropic cytokine triggering cell responses through two distinct membrane receptors. Stimulation of leukocyte adhesion to the endothelium is one of the many TNF-alpha activities and is explained by the upregulation of adhesion molecules on the endothelial cell surface. Human umbilical vein endothelial cells (HUVEC) were isolated, cultured, and demonstrated to express both TNF receptor types, TNF-R55 and TNF-R75. Cell adhesion to HUVEC was studied using the HL60, U937, and MOLT-4 cell lines. HUVEC were activated by either TNF-alpha, binding to both TNF-R55 and TNF-R75, and by receptor type-specific agonists, binding exclusively to TNF-R55 or to TNF-R75. The TNF-alpha-induced cell adhesion to HUVEC was found to be controlled almost exclusively by TNF-R55. This finding correlated with the exclusive activity of TNF-R55 in the TNF-alpha-dependent regulation of the expression of the intercellular adhesion molecule type 1 (ICAM-1), E-selectin, and vascular cell adhesion molecule type 1 (VCAM-1). The CD44 adhesion molecule in HUVEC was also found to be upregulated through TNF-R55. However, both TNF-R55 and TNF-R75 upregulate alpha 2 integrin expression in HUVEC. The predominant role of TNF-R55 in TNF-alpha-induced adhesion in HUVEC may correlate with its specific control of NF-kappa B activation, since kappa B elements are known to be present in ICAM-1, E-selectin, and VCAM-1 gene regulatory sequences.

Base Sequence↗

PubMed1992

Both tumor necrosis factor receptor types mediate proliferative signals in human mononuclear cell activation.

TNF is a highly pleiotropic cytokine. The recent identification of two distinct cellular receptors for TNF may provide explanations for the many different TNF activities. We have investigated the expression of the two receptor types, TNFR alpha (75 kDa) and TNFR beta (55 kDa), in human PBMC. Both receptors were found simultaneously expressed by cytofluorimetric, radioligand binding and Northern analysis of naive as well as PHA-activated PBMC. The expression levels in the CD14+ and CD14- subsets were different. Both receptors were strongly expressed in the CD14+ subset. The expression of the receptors in the CD14-, CD3+, CD4+, and CD8+ subsets was lower and similar among these subsets, but TNFR alpha was expressed at higher level than TNFR beta. To dissect the functional roles of the two receptors, we studied the growth factor activity of TNF in the late proliferative responses of PBMC to PHA. In the first approach, the activity of either receptor was blocked by neutralizing, receptor type specific antibodies. In a second approach, the ligand, TNF, was inhibited by a neutralizing antiserum, and the cells were restimulated using type-specific anti-TNFR antibodies with agonistic activity. It was found that both receptor types mediated signals required for proliferative responses of PBMC to PHA from day 4 to day 8 in culture. The cell responses to the activation of either receptor type appeared to be independent, because one receptor could not compensate for the reduction in cell activation caused by blocking the other receptor type.

Antibodies, Monoclonal↗

PubMed1992

Cytokines, receptors, and inhibitors.

Cytokines are endogenous mediators in inflammatory and immunologic host defense reactions. In various diseases cytokines produced in excess cause systemic or local toxic effects. Cytokines therefore are tightly controlled by regulation of their biosynthesis and release and by counteracting mechanisms which limit their activities. Two new cytokine inhibitory mechanisms have recently been discovered. First, the generation of soluble receptors which compete with cellular receptors for cytokine binding has been recognized as a general phenomenon. Second, a receptor antagonist polypeptide binding to the receptor but not eliciting biological activity has been discovered in the IL-1 system. These polypeptides, when expressed in various recombinant forms, are not only research tools but may find also direct clinical use.

Cytokines↗

PubMed1992

Tumor necrosis factor receptors--structure and function.

Tumor necrosis factors (TNFs) have been a focus of research for well over a decade now. The identification and recent molecular cloning of two different types of cell-surface TNF receptors will shed further light on the mode of action of these pleiotropic cytokines. In the present article, we summarize the data on the biochemistry and structure of the receptors and focus on the molecular cloning of the respective cDNAs. The nucleotide sequences of the receptor genes revealed that both TNF receptors belong to the still growing nerve growth factor receptor gene family. The function and origin of TNF inhibitory proteins as well as receptor-mediated signal transduction are discussed.

Animals↗