QS402. IL-6 Synergizes With T Helper II Cytokines to Up-Regulate Arginase I in Spleen Myeloid Suppressor Cells Following Traumatic Stress

Abstract

Introduction: Accidental or surgical traumatic stress causes immune dysfunction associated with increased infection rates and high morbidity and mortality. We have recently demonstrated that trauma-induced immature myeloid suppressor CD11b+/Gr-1+ cells (TIIMSC) accumulate in the spleen, expressing high levels of arginase I and causing T-cell dysfunction by depleting L-arginine. Factors that might lead to increased arginase activity in splenic CD11b+/Gr-1+ cells after trauma are not known. Methods: Plasma was harvested from mice at different time points after trauma and cytokine levels were quantified using luminex assay. CD11b+/Gr-1+ cells were harvested from the spleens and cultured in the presence of IL-4, IL-5, IL-6, IL-10, IL-13 and TGF-β. Arginase activity was measured through a colorimetric assay. Results: in this report we provide evidence that IL-6 and IL-5 are both temporarily increased in the blood after trauma (IL-6, 179±91pg/ml, peak at 3h; IL-5, 110±64pg/ml, peak at 12h). In contrast to the known stimulatory effects of IL-4 and IL-13, neither IL-5 nor IL-6 induced arginase activity in splenic CD11b+ cells. However, IL-6 induced a significant additional increase in arginase I expression and activity in combination with low doses of either IL-4 (2266±312 vs. 354±39, p<0.01) or IL-13 (1955±293 vs. 260±41, p<0.01). This synergistic induction of arginase was much more potent than the effect of two other known arginase-inducing cytokines, IL-10 (776±81) and TGF-β (594±66). IL-5 not only failed to synergize with either IL-4 or IL-13, but in fact antagonized the stimulatory activity of IL-6. Injection of IL-6 in control animals resulted in a modest increase in both arginase activity and sensitivity to IL-4 and IL-13 in splenic CD11b+ cells, but failed to reach the levels induced by trauma. Finally, detected plasma IL-6 level positively correlated (R2=0.903) with the increase in arginase activity in spleen CD11b+ cells. Conclusion: Our results define a novel role for IL-6 after trauma, suggesting that this cytokine is necessary but not sufficient for arginase increase in spleen CD11b+/Gr-1+ cells. By influencing arginase I activity in TIIMSC, IL-6 plays an important role in creating trauma induced immune deficiency.