Differential regulation of lymphotoxin (LT), lymphotoxin-beta (LT-beta), and TNF-alpha in murine T cell clones activated through the TCR.
The present study demonstrates differential regulation of three members of the TNF family, lymphotoxin (LT), LT-beta, and TNF-alpha, by activated murine T cell clones. We report for the first time that murine T cells transcribe LT-beta mRNA in the absence of any activating signal. Activation through the TCR by anti-CD3 did not increase the accumulation of LT-beta mRNA but did increase the accumulation of two species of TNF-alpha mRNA and three species of LT mRNA. We determined that anti-CD3-activated T cells differ in their regulation of LT, LT-beta, and TNF-alpha at the transcriptional and post-transcriptional levels. Anti-CD3 activation resulted in substantial increases in the extent of transcription of the TNF-alpha and LT genes, although with different rates. LT mRNA accumulation was also post-transcriptionally regulated by anti-CD3. In anti-CD3-activated T cells, the t1/2 of LT mRNA was three to four times longer than that of TNF-alpha mRNA. LT-beta mRNA decayed at a rate similar to that of LT mRNA. We also noted a dramatic difference in the cycloheximide sensitivity of LT, LT-beta, and TNF-alpha mRNAs. Cycloheximide superinduced the accumulation of LT mRNA, but not that of TNF-alpha and LT-beta mRNA, post-transcriptionally. Thus, this study demonstrates dramatic differences in the molecular mechanisms of regulation of LT, LT-beta, and TNF-alpha. It also indicates that LT production is probably the rate-limiting step in the formation of the LT-LT-beta complex. These differences suggest that the reason for the redundancy of LT, LT-beta, and TNF-alpha is their differential regulation rather than their functions.
Millet
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I
Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT 06520.
Ruddle
N H
NH
D000818:Animals; D017252:CD3 Complex; D002999:Clone Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D005786:Gene Expression Regulation; D007700:Kinetics; D008213:Lymphocyte Activation; D008233:Lymphotoxin-alpha / Q000235:genetics*; D051379:Mice; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D017252:CD3 Complex; D008233:Lymphotoxin-alpha; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide