Autocrine Tumor Necrosis Factor (TNF) and Lymphotoxin (LT) α Differentially Modulate Cellular Sensitivity to TNF/LT-α Cytotoxicity in L929 Cells

Abstract

Tumor necrosis factor (TNF) and lymphotoxin (LT) α are structurally and functionally related cytokines. We expressed the TNF and LT-α genes in murine fibrosarcoma L929r2 cells, which can be sensitized to TNF/LT-α–dependent necrosis by inhibitors of transcription or translation. Autocrine production of murine TNF in L929r2 cells completely downmodulated the expression of the 55- and 75-kD TNF receptors, resulting in resistance to TNF/LT-α cytotoxicity. Partial downmodulation of the 55-kD receptor was observed in human TNF-producing L929r2 cells. In contrast, an unaltered TNF receptor expression was found on LT-α L929r2 transfectants. Hence, although similar cytotoxic effects are induced by extracellularly administered TNF and LT-α, endogenous expression of these cytokines fundamentally differs in the way they modulate TNF receptor expression. Unlike LT-α, secreted by the classical pathway, TNF is first formed as a membrane-bound protein, which is responsible for receptor downmodulation. To explore whether the different pathways for secretion of TNF and LT-α explain this difference, we examined the effect of membrane-bound LT-α expression. This was obtained by exchange of the classical signal sequence of LT-α for the membrane anchor of chicken hepatic lectin. Membrane retention of LT-α resulted indeed in receptor downmodulation and TNF/LT-α resistance. We conclude that membrane retention of newly synthesized TNF or LT-α is absolutely required for receptor downmodulation and TNF/LT-α resistance.

Vascular Endothelial Growth Factor KDR Receptor Signaling Potentiates Tumor Necrosis Factor-induced Tissue Factor Expression in Endothelial Cells

“…TNF-␣ and TNF-␤ are structurally similar, but TNF-␣ binds to the TNFR60 receptor with higher affinity (31). Our data are consistent with this observation in that VEGF/TNF-␣ induced a higher TF expression relative to VEGF/TNF-␤.…”

“…It is also involved in early wound healing, angiogenesis, and tumor metastasis (31)(32)(33). Normally, TF is not expressed on the surface of cells that are in direct contact with blood such as the endothelium lining vessels and circulating monocytes; however, growth factors and cytokines may induce TF expression in these cells (25)(26)(27).…”

Role of TNF-α signaling in regeneration of cardiotoxin-injured muscle

“…To assess the role of TNF-␣ in muscle regeneration, we chose to conduct the studies in p55 Ϫ/Ϫ p75 Ϫ/Ϫ mice instead of TNF-␣-knockout mice to ensure the complete absence of TNF-␣ signaling, considering that lymphotoxin-␣ can activate TNF-␣ receptors (11) and that oligomerization of TNF-␣ receptors can occur in the absence of ligand binding, leading to receptor activation without actual ligand-receptor interaction (14). Muscle regeneration in soleus muscle was induced by direct injection of CTX derived from snake venom, which induces extensive and reproducible muscle necrotic injury.…”

The Role of Tumor Necrosis Factor-alpha (TNF-α) in Skeletal Muscle Regeneration

“…LT-␣ has similar proinflammatory effects to TNF-␣ but exerts only a partial agonistic effect (Decoster et al 1998). LT-␣ is of primarily B-and T-lymphocyte origin, and can exist in a soluble homotrimeric form or in membrane-bound heterotrimeric form in complex with lymphotoxinbeta (LT-␤ ) (Decoster et al 1998) (see Figure 1B).…”