Acute Hemorrhagic Necrosis of Tumors Induced by Interleukin-1  Effects Independent of Tumor Necrosis Factor

Abstract

Tumor necrosis factor (TNF), a protein synthesized in response to the endotoxin bacterial lipopolysaccharide (LPS), is the classical mediator of acute hemorrhagic necrosis of tumors. We have demonstrated that interleukin-1 alpha (IL-1 alpha), with a spectrum of activities very similar to those of TNF, also causes acute hemorrhagic necrosis of tumors. Both TNF and IL-1 induce a cascade of events including the synthesis or release of each other. The present studies were thus undertaken to determine whether the hemorrhagic necrosis induced in tumors by IL-1 alpha is due to TNF. Kinetic parameters of IL-1 alpha-induced hemorrhage were similar to those observed with recombinant murine TNF-alpha (TNF-alpha) or LPS in RIF-1 fibrosarcomas in C3H/HeN (endotoxin-sensitive) mice. However, the amount of TNF found in the sera or tumors of animals treated with LPS was more than 20-fold higher than in mice treated with IL-1 alpha, and LPS induced similar degrees of hemorrhagic necrosis, which was measured by determining the packed volume of red blood cells by 59Fe labeling. A low but significantly hemorrhagic dose of IL-1 alpha induced no detectable TNF in tumors. Pretreatment with 250 micrograms of neutralizing antibody to TNF had no effect on IL-1 alpha-induced hemorrhage, whereas TNF-alpha- and LPS-induced hemorrhagic effects were significantly reduced. These results demonstrate an important antitumor activity of IL-1 alpha that appears to be independent of TNF.

The antitumour activity of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in TNF receptor-1 knockout mice

“…The nature of the agent(s) involved is currently unknown, but other agents known to induce tumour haemorrhagic necrosis include interferons a/b (Dvorak and Gresser, 1989), interleukin-1a (Johnson et al, 1991), IP-10 (Sgadari et al, 1996), serotonin (Manda et al, 1988) and nitric oxide (Fukumura et al, 1997). DMXAA is known to induce interferons (Pang et al, 1998), IP-10 (Cao et al, 2001), serotonin (Baguley et al, 1993(Baguley et al, , 1997 and nitric oxide (Thomsen et al, 1991).…”

Gomisin A Enhances Tumor Necrosis Factor-α-Induced G1 Cell Cycle Arrest <i>via</i> Signal Transducer and Activator of Transcription 1-Mediated Phosphorylation of Retinoblastoma Protein

“…[25][26][27] Tumor necrosis factor-α (TNF-α) causes a hemorrhagic necrotic effect against implanted solid tumors. [28][29][30][31] Nuclear factor (NF)-κB has been well understood to prevent the pro-apoptotic effect of TNF-α. 32,33) We previous demonstrated that gomisin N, but not gomisin A, inhibited the TNF-α-induced NF-κB and epidermal growth factor receptor (EGFR) signaling pathways in HeLa cells, which resulted in enhanced pro-apoptotic events.…”