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Fibrosarcoma‐induced increase in macrophage tumor necrosis factor α synthesis suppresses T cell responses
Author(s) -
Alieva David G.,
Askew David,
Burger Carol J.,
Elgert Klaus D.
Publication year - 1993
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.54.2.152
Subject(s) - fibrosarcoma , biology , macrophage , tumor necrosis factor alpha , tumor necrosis factor α , necrosis , cancer research , ht1080 , microbiology and biotechnology , immunology , biochemistry , in vitro , genetics
Tumors down‐regulate T cell responses partly by increasing macrophage (m φ) production of the suppressive molecule prostaglandin E 2 (PGE 2 ). Because tumor growth increases m φ tumor necrosis factor a (TNF‐α) production and TNF‐α stimulates m φ PGE 2 synthesis, we examined the contribution of TNF‐α to fibrosarcoma‐induced m φ ‐mediated suppression of allo‐ reactive CD4 + T cell proliferation. We showed that tumorbearing host (TBH) m φs express high levels of TNF‐α mRNA, which leads to increased lipopolysaccharide‐ induced TNF‐α production. Timor cells were directly involved in m φ TNF‐α synthesis because fibrosarcoma cells induced normal host (NH) m φ s to produce TNF‐α. Addition of TBH m φ s to allogeneic mixed lymphocyte reaction (MLR) cultures suppressed CD4 + T cell proliferation more than NH m φ s. The neutralization of endogenous TNF‐α activity with anti‐TNF‐α antibody (Ab) treatment reversed TBH, but not NH, m φ ‐mediated suppression. Conversely, exogenous TNF‐α increased NH or TBH mφ‐mediated suppression but stimulated T cell proliferation without m φ s. Kinetic treatment of MLR cultures with anti‐TNF‐α Ab or TNF‐α showed that TNF‐ αproduction and activity occurred at the beginning of T cell proliferation. When arachidonic acid metabolite synthesis was inhibited, TNF‐α‐induced suppression was blocked in NH m φ ‐containing cultures and completely reversed in TBH mφ‐containing cultures. A PGErspecific enzyme‐linked immunosorbent assay showed that TNF‐a addition increased PGE 2 production in NH m φ ‐ containing cultures to that of TBH m φ ‐containing cultures. Exogenous PGE 2 did not affect the TNF‐α enhancement of T cell proliferation without m φ s. Therefore, suppression induced by TNF‐α was caused by increased m φ PGE 2 production and not by TNF‐α in concert with PGE 2 . Even though TNF‐a is known to enhance lymphocyte proliferation, we show that in the presence of mφs, the main TNF‐α producers, TNF‐α suppresses T cell proliferation. Perhaps increased TNF‐α production during pathological states, such as cancer, triggers the initial stages of suppression.