Increased tumor necrosis factor alpha (TNF alpha), interleukin 1, and interleukin 6 (IL-6) levels in the plasma of stored platelet concentrates: relationship between TNF alpha and IL-6 levels and febrile transfusion reactions

Tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) activate transcription of the TSG-6 gene in normal human fibroblasts through a promoter region (-165 to -58) that encompasses an AP-1 and a NF-IL6 site. We show by deletion analysis and substitution mutagenesis that both sites are necessary for activation by TNF-alpha. Activation by IL-1 requires the NF-IL6 site and is enhanced by the AP-1 site. These results suggest that the NF-IL6 and AP-1 family transcription factors functionally cooperate to mediate TNF-alpha and IL-1 signals. Consistent with this possibility, IL-1 and TNF-alpha markedly increase the binding of Fos and Jun to the AP-1 site, and NF-IL6 activates the native TSG-6 promoter. Activation by NF-IL6 requires an intact NF-IL6 site and is modulated by the ratio of activator to inhibitor NF-IL6 isoforms that are translated from different in-frame AUGs. However, the inhibitor isoform can also bind to the AP-1 site and repress AP-1 site-mediated transcription. The finding that the inhibitor isoform antagonizes activation of the native TSG-6 promoter by IL-1 and TNF-alpha suggests that NF-IL6 has a physiologic role in these cytokine responses. Thus, the functionally distinct NF-IL6 isoforms cooperate with Fos and Jun to positively and negatively regulate the native TSG-6 promoter by TNF-alpha and IL-1.

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Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes.

Journal of Experimental Medicine ◽

10.1084/jem.173.3.699 ◽

1991 ◽

Vol 173 (3) ◽

pp. 699-703 ◽

Cited By ~ 787

Author(s):

E P Sampaio ◽

E N Sarno ◽

R Galilly ◽

Z A Cohn ◽

G Kaplan

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Interleukin 1 ◽

Human Monocyte ◽

Tnf Alpha ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Necrosis Factor

Thalidomide selectively inhibits the production of human monocyte tumor necrosis factor alpha (TNF-alpha) when these cells are triggered with lipopolysaccharide and other agonists in culture. 40% inhibition occurs at the clinically achievable dose of the drug of 1 micrograms/ml. In contrast, the amount of total protein and individual proteins labeled with [35S]methionine and expressed on SDS-PAGE are not influenced. The amounts of interleukin 1 beta (IL-1 beta), IL-6, and granulocyte/macrophage colony-stimulating factor produced by monocytes remain unaltered. The selectivity of this drug may be useful in determining the role of TNF-alpha in vivo and modulating its toxic effects in a clinical setting.

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NF-IL6 and AP-1 cooperatively modulate the activation of the TSG-6 gene by tumor necrosis factor alpha and interleukin-1.

Molecular and Cellular Biology ◽

10.1128/mcb.14.10.6561 ◽

1994 ◽

Vol 14 (10) ◽

pp. 6561-6569 ◽

Cited By ~ 53

Author(s):

L Klampfer ◽

T H Lee ◽

W Hsu ◽

J Vilcek ◽

S Chen-Kiang

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Interleukin 1 ◽

Human Fibroblasts ◽

Tnf Alpha ◽

Necrosis Factor Alpha ◽

Normal Human ◽

Factor Alpha ◽

Necrosis Factor

Tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) activate transcription of the TSG-6 gene in normal human fibroblasts through a promoter region (-165 to -58) that encompasses an AP-1 and a NF-IL6 site. We show by deletion analysis and substitution mutagenesis that both sites are necessary for activation by TNF-alpha. Activation by IL-1 requires the NF-IL6 site and is enhanced by the AP-1 site. These results suggest that the NF-IL6 and AP-1 family transcription factors functionally cooperate to mediate TNF-alpha and IL-1 signals. Consistent with this possibility, IL-1 and TNF-alpha markedly increase the binding of Fos and Jun to the AP-1 site, and NF-IL6 activates the native TSG-6 promoter. Activation by NF-IL6 requires an intact NF-IL6 site and is modulated by the ratio of activator to inhibitor NF-IL6 isoforms that are translated from different in-frame AUGs. However, the inhibitor isoform can also bind to the AP-1 site and repress AP-1 site-mediated transcription. The finding that the inhibitor isoform antagonizes activation of the native TSG-6 promoter by IL-1 and TNF-alpha suggests that NF-IL6 has a physiologic role in these cytokine responses. Thus, the functionally distinct NF-IL6 isoforms cooperate with Fos and Jun to positively and negatively regulate the native TSG-6 promoter by TNF-alpha and IL-1.

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Mechanism underlying tumor necrosis factor-alpha suppression of norepinephrine release from rat myenteric plexus

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1994.266.6.g1123 ◽

1994 ◽

Vol 266 (6) ◽

pp. G1123-G1129 ◽

Cited By ~ 8

Author(s):

S. M. Hurst ◽

S. M. Collins

Keyword(s):

Protein Synthesis ◽

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Myenteric Plexus ◽

Tumor Necrosis ◽

Interleukin 1 ◽

Tnf Alpha ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Necrosis Factor

We studied the effect of tumor necrosis factor-alpha (TNF-alpha) on the release of [3H]norepinephrine ([3H]NE) from longitudinal muscle-myenteric plexus preparations of rat jejunum. TNF-alpha had no immediate effect on [3H]NE release. Preincubation of the tissue with TNF-alpha caused a suppression of [3H]NE release stimulated by KCl or electrical field stimulation. The action of TNF-alpha was time and concentration dependent (0.1-50 ng/ml) and was not due to endotoxin contamination. The effect of TNF-alpha was biphasic, occurring after 30 min and again after 120 min of preincubation. The early component was independent of protein synthesis but was inhibited by piroxicam or indomethacin, indicating the involvement of cyclooxygenase metabolites. The late component was dependent on protein synthesis, was blocked by an interleukin-1 receptor antagonist, and was inhibited by piroxicam or indomethacin. These results indicate that TNF-alpha suppresses NE release by two mechanisms, one of which is due to the synthesis and release of interleukin-1, each involving arachidonic acid metabolites.

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