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ERK and Not p38 Pathway Is Required for IL-12 Restoration of T Cell IL-2 and IFN- in a Rodent Model of Alcohol Intoxication and Burn Injury¹

Xiaoling Li^*, Irshad H. Chaudry and Mashkoor A. Choudhry^2,*

^* Burn and Shock Trauma Institute and Alcohol Research Program, Department of Surgery, Loyola University Chicago Medical Center, Maywood, IL 60153; and Center for Surgical Research and Departments of Surgery, University of Alabama, Birmingham, AL 35226

Previous studies from our laboratory have shown that acute alcohol/ethanol (EtOH) intoxication combined with burn injury suppresses T cell IL-2 and IFN- production by inhibiting p38 and ERK activation. Because IL-12 plays a major role in Th1 differentiation and IFN- production, we examined whether diminished IL-2 and IFN- production after EtOH plus burn injury resulted from a decrease in IL-12. Furthermore, we investigated whether IL-12 utilizes the p38/ERK pathway to modulate T cell IL-2 and IFN- production after EtOH and burn injury. Male rats (250 g) were gavaged with 5 ml of 20% EtOH 4 h before 12.5% total body surface area burn or sham injury. Rats were sacrificed on day 1 after injury, and mesenteric lymph node T cells were isolated. T cells were stimulated with anti-CD3 in the absence or presence of rIL-12 (10 ng/ml) for 5 min and lysed. Lysates were analyzed for p38/ERK protein and phosphorylation levels using specific Abs and Western blot. In some experiments, T cells were cultured for 48 h with or without the inhibitors of p38 (10 µM SB203580/SB202190) or ERK (50 µM PD98059) to delineate the role of p38 and ERK in IL-12-mediated restoration of IL-2 and IFN-. Our findings indicate that IL-12 normalizes both p38 and ERK activation in T cells, but the results obtained using p38 and ERK inhibitors indicate that the restoration of ERK plays a predominant role in IL-12-mediated restoration of T cell IL-2 and IFN- production after EtOH and burn injury.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study is supported by National Institutes of Health Grant R01AA015731.

² Address correspondence and reprint requests to Dr. Mashkoor A. Choudhry, Burn and Shock Trauma Institute, Building 110/Emergency Medical Services, Room 4236, Loyola University Chicago Medical Center, 2160 South First Avenue, Maywood, IL 60153. E-mail address: mchoudhry{at}lumc.edu

³ Abbreviations used in this paper: EtOH, alcohol/ethanol; MLN, mesenteric lymph node; TBST, TBS supplemented with 0.05% Tween 20; SB, SB203580 or SB202190; PD, PD98059; TBSA, total body surface area; MKK, megakaryocytic protein tyrosine kinase; ATF, activating transcription factor.