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Title: Altered gene transcription after burn injury results in depressed T-lymphocyte activation.
Author: Horgan AF, Mendez MV, O'Riordain DS, Holzheimer RG, Mannick JA, Rodrick ML.
Journal: Ann Surg; 1994 Sep; 220(3):342-51; discussion 351-2. PubMed ID: 8092900.
Abstract:
OBJECTIVE: Patients with major burns and an animal model of burn injury were studied to determine the mechanism of depressed interleukin-2 (IL-2) production after thermal injury and to determine the effect of such injury on IL-2 receptor (IL-2R) expression and function. SUMMARY BACKGROUND DATA: Major burn injury is known to diminish resistance to infection by altering cytokine production and prostanoic secretion and by inhibiting T-lymphocyte activation. T-cell activation requires production of regulatory cytokines, principally IL-2, and expression of the appropriate cytokine receptors. Depressed IL-2 production after major burn injury is undisputed, although the molecular mechanisms remain undefined; the effect of burn injury on IL-2R expression and function currently is controversial. METHODS: The authors studied serial samples of peripheral blood mononuclear cells (PBMC) from 11 patients with 25% to 95% surface area burns and 7 age-matched volunteer control subjects. Peripheral blood mononuclear cells were stimulated by the T-cell mitogen phytohemagglutinin (PHA), and IL-2 production and mRNA expression by Northern blot were determined. Expression and function of IL-2R were determined by monoclonal antibodies to the p55 and p75 chains of the IL-2R, binding of fluorescein-labeled IL-2, and response to exogenous recombinant IL-2. We also studied a mouse model of 20% burn injury known to mimic the immune abnormalities seen in humans with burns. Splenocytes from mice with burns (20-22 per group) were studied for IL-2 production and IL-2 mRNA expression after stimulation with the T-cell mitogen concanavalin A (ConA) and compared with sham burn control subjects. Kinetics of mRNA expression after ConA stimulation also were determined and a nuclear run-on assay performed to determine IL-2 gene transcription. The mRNA expression was determined for the proto-oncogenes c-jun and c-fos, whose protein products join to form transcription factor AP1, which is necessary for activation of the IL-2 promoter. Splenocytes from mice with burns after ConA stimulation also were studied for expression and function of the IL-2R. RESULTS: Peripheral blood mononuclear cells from burn patients compared with healthy control subjects showed diminished (p < 0.05) IL-2 production and mRNA expression 4 to 10 days after burn injury. Burn PBMC demonstrated normal expression of IL-2R, p55, and p75 chains 0 to 7, 8 to 20, and 21 to 37 days after burn injury, normal IL-2R binding of fluorescein-labeled IL-2, and a normal proliferative response to PHA in the presence of exogenous recombinant IL-2. Splenocytes from mice 7 days after burn injury showed diminished production (p < 0.05) of IL-2 and IL-2 mRNA expression after ConA stimulation as compared with sham burn control subjects. Kinetics of mRNA expression after ConA stimulation were the same for burn and control mice, indicating that reduced IL-2 mRNA expression was not caused by altered mRNA degradation. A nuclear run-on assay confirmed decreased IL-2 gene transcription in burn splenocytes. Burn splenocytes showed normal expression of mRNA for c-jun but diminished expression of mRNA for c-fos. Finally, splenocytes from mice with burns after ConA stimulation showed normal expression and function of the IL-2R 7, 10, 14, and 21 days after burn injury. CONCLUSIONS: These human and animal studies indicate that major burn injury depresses T-cell activation at the level of IL-2 gene transcription at least in part by inhibiting c-fos expression, whereas IL-2R expression and function remain normal and T-cell proliferation can be restored to normal levels by exogenous IL-2.

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