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Transforming growth factor‐β negatively modulates T‐cell responses in sepsis
Author(s) -
Ahmad Sarfraz,
Choudhry Mashkoor A,
Shankar Ravi,
Sayeed Mohammed M
Publication year - 1997
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(96)01535-9
Subject(s) - sepsis , cytokine , biology , bacteroides fragilis , splenocyte , concanavalin a , transforming growth factor , t cell , intracellular , tumor necrosis factor alpha , lipopolysaccharide , microbiology and biotechnology , immunology , endocrinology , spleen , immune system , biochemistry , in vitro , antibiotics
Sepsis is associated with depressed T‐cell functions and increased circulating levels of immunosuppressive agents. TGF‐β is a potential anti‐inflammatory cytokine that can modify T‐cell growth and differentiation. The up‐regulation of TGF‐β and the mechanism of its action on the T‐cells during septic injury have not been resolved. We hypothesized that in sepsis TGF‐β produced by macrophages acts on T‐cells in a paracrine manner to suppress interleukin (IL)‐2 production and proliferation. In this study, we examined the circulating TGF‐β levels in a rat model of Gram‐negative bacterial sepsis, and compared the abilities of adherent and non‐adherent splenocytes to produce TGF‐β. Additionally, we investigated the causal relationships of hrTGF‐β to concanavalin A (ConA)‐induced T‐cell responses and the intracellular mechanism of the generation of these responses in normal splenic rat T‐cells. Sepsis was induced in rats by intra‐abdominally implanting fecal pellets containing Escherichia coli (150 CFU) and Bacteroides fragilis (10 000 CFU). Adherent and non‐adherent splenocytes were isolated by differential adherence using Ficoll gradient centrifugation. T‐cells were purified by use of Nylon wool columns. We observed a 3–6‐fold increase in the circulating levels of TGF‐β in sepsis. Western blots and ELISA determinations revealed a 2.5–3‐fold increase in cell‐associated TGF‐β protein levels in adherent splenic cells. Northern analyses also showed a marked increase in TGF‐β mRNA expression in adherent cells during sepsis. On the other hand, a significant change was not observed in the TGF‐β protein and mRNA expression in non‐adherent splenocytes. Pretreatment of control rat T‐cells with hrTGF‐β decreased both ConA‐induced proliferation (by 35–40%) and IL‐2 mRNA expression (by >50%). Further, whereas incubation of control rat T‐cells with either ConA or TGF‐β for 24 h resulted in a 10–15‐fold increase in cAMP generation, the addition of hrTGF‐β along with ConA resulted in a 50–60‐fold increase in cAMP. These results suggest that in sepsis, TGF‐β produced by splenic macrophages can act in a paracrine manner on T‐cells to depress their IL‐2 mRNA expression, IL‐2 production and proliferation after up‐regulation of cAMP which can interfere with T‐cell signaling for proliferation.