[PDF][PDF] Tumor growth increases Ia^-macrophage synthesis of tumor necrosis factor and prostaglandin E~ 2: changes in macrophage suppressor activity

DG Alleva, CJ Burger, KD Elgert - Journal of leukocyte biology, 1993 - Citeseer
DG Alleva, CJ Burger, KD Elgert
Journal of leukocyte biology, 1993Citeseer
Although tumor growth enhances macrophage (mcb) cytotoxic activity by increasing their
tumor necrosis factor-a (TNF-a) production, increased prostaglandin E2 (PGE2) synthesis
reduces most immune responses during tumor growth. Macrophages that do not express
major histocompatibility complex class II molecules(1a m) are the predominant suppressor
and cytotoxic population and are more abundant in tumor-bearing hosts (TBHs). This study
determined if TBH Il mqis are the major population producing TNF-a and PGE2 and if these …
Abstract
Although tumor growth enhances macrophage (mcb) cytotoxic activity by increasing their tumor necrosis factor-a (TNF-a) production, increased prostaglandin E2 (PGE2) synthesis reduces most immune responses during tumor growth. Macrophages that do not express major histocompatibility complex class II molecules(1a m) are the predominant suppressor and cytotoxic population and are more abundant in tumor-bearing hosts (TBHs). This study determined if TBH Il mqis are the major population producing TNF-a and PGE2 and if these molecules affect 1a mgi-mediated suppression of alloantigen-stimulated T cell proliferation. Normal host (NH) and TBH splenic Ia-depleted(1a) ms synthesized more TNF-a than their respective whole populations (WPs) when cultured with lipopolysaccharide and interferon--1. TBH Ia ms produced the most TNF-a. Northern blot analyses showed that 1a m#{231} lsshad higher amounts of TNF-a mR. NA expression than their respective WP, and TBH Il m4s expressed the highest amounts of TNF-a mRNA. When WP and 1a NH and TBH mcbs were added to alloantigen-stimulated T cells, suppression of T cell proliferation mediated by 1a mcts was greater than by their respective WP. TBH 1a mqs were most suppressive. The blockage of PGE2 production reduced suppression mediated by TBH Ia mqs more than by all other m4 populations. A PGE2-specific enzyme-linked immunosorbent assay showed that PGE2 production was greater in 1a m-than in WP m4i-containing cultures and greatest in cultures containing TBH 1a ms. Because TNF-a enhances T cell responses, its effects on Ia m4 PGrE,-mediated suppression was determined. When TNF-a was added to mi-containing T cell cultures, TNF-a directly stimulated NH, but not TBH, Ia m4s, which enhanced T cell proliferation. However, inhibiting PGE2 production allowed TNF-a to stimulate T cell proliferation in TBH 1a m4-containing cultures. Collectively, these data show that 1a mcs are the major TNF-a-and PGE2-producing cells and that these molecules are partly responsible for the tumor-induced increase in m4-mediated cytotoxicity and suppression, respectively. TNF-a not only mediates cytotoxicity but also counteracts 1a m4 PGE2-mediated suppression. Although tumor growth increases Ia m TNF-a production, enhanced PGE2 production blocks TNF-a’s stimulatory action on 1a m4s, which favors their suppressor function during tumor growth. J. Leukoc. Biol. 53: 550-558; 1993.
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