TY - JOUR

T1 - Interleukin-1 receptor antagonist reverses stroke-associated peripheral immune suppression

AU - Smith, Craig J.

AU - Emsley, Hedley C.

AU - Udeh, Chinedu T.

AU - Vail, Andy

AU - Hoadley, Margaret E.

AU - Rothwell, Nancy J.

AU - Tyrrell, Pippa J.

AU - Hopkins, Stephen J.

PY - 2012/6

Y1 - 2012/6

N2 - Introduction: Infections are common following stroke and adversely affect outcome. Cellular immune suppression associated with acute stroke may increase susceptibility to infection. Cytokines are important contributors to both stroke pathology and the response to infection. Since interleukin (IL)-1 blockade is a candidate treatment for cerebral ischemia, we examined whether administration of interleukin-1 receptor antagonist (IL-1Ra) to patients with acute stroke affected innate cellular immune responses in a phase II placebo-controlled trial. Methods: Venous blood samples were taken prior to treatment initiation, at 24. h and 5 to 7d. Blood was also drawn from stroke-free controls. Lipopolysaccharide (LPS) stimulation of whole-blood cultures assessed the potential of leukocytes to produce cytokines. Results: Induction of tumor necrosis factor (TNF)-α, IL-1β, IL-6, IL-8 and IL-10 by LPS was significantly reduced in patients at admission, compared to controls. At 24. h, cytokine induction remained suppressed in the placebo group. In contrast, for patients treated with IL-1Ra, induction of TNF-α, IL-6 and IL-10 was similar to controls and IL-1β induction was significantly greater than in the placebo group. At 5 to 7d, TNF-α and IL-1β induction remained suppressed only in the placebo group (p<0.05). Plasma cortisol concentrations, elevated at admission in patients compared to controls, were substantially reduced at 24. h in the patients receiving IL-1Ra (p<0.05) and inversely correlated (p<0.001) with either TNF-α (r=. -0.71) or IL-1β induction (r=. -0.67) at admission. Conclusion: Treatment with IL-1Ra reverses peripheral innate immune suppression in the acute phase of stroke, which is associated with attenuated cortisol production. The mechanisms underlying these observations, including the potential impact of IL-1Ra on stroke severity and the clinical significance of immune suppression, require further evaluation in larger studies. 

AB - Introduction: Infections are common following stroke and adversely affect outcome. Cellular immune suppression associated with acute stroke may increase susceptibility to infection. Cytokines are important contributors to both stroke pathology and the response to infection. Since interleukin (IL)-1 blockade is a candidate treatment for cerebral ischemia, we examined whether administration of interleukin-1 receptor antagonist (IL-1Ra) to patients with acute stroke affected innate cellular immune responses in a phase II placebo-controlled trial. Methods: Venous blood samples were taken prior to treatment initiation, at 24. h and 5 to 7d. Blood was also drawn from stroke-free controls. Lipopolysaccharide (LPS) stimulation of whole-blood cultures assessed the potential of leukocytes to produce cytokines. Results: Induction of tumor necrosis factor (TNF)-α, IL-1β, IL-6, IL-8 and IL-10 by LPS was significantly reduced in patients at admission, compared to controls. At 24. h, cytokine induction remained suppressed in the placebo group. In contrast, for patients treated with IL-1Ra, induction of TNF-α, IL-6 and IL-10 was similar to controls and IL-1β induction was significantly greater than in the placebo group. At 5 to 7d, TNF-α and IL-1β induction remained suppressed only in the placebo group (p<0.05). Plasma cortisol concentrations, elevated at admission in patients compared to controls, were substantially reduced at 24. h in the patients receiving IL-1Ra (p<0.05) and inversely correlated (p<0.001) with either TNF-α (r=. -0.71) or IL-1β induction (r=. -0.67) at admission. Conclusion: Treatment with IL-1Ra reverses peripheral innate immune suppression in the acute phase of stroke, which is associated with attenuated cortisol production. The mechanisms underlying these observations, including the potential impact of IL-1Ra on stroke severity and the clinical significance of immune suppression, require further evaluation in larger studies. 

KW - Acute stroke

KW - Immune suppression

KW - Infection

KW - Inflammation

KW - Interleukin-1 receptor antagonist

U2 - 10.1016/j.cyto.2012.02.016

DO - 10.1016/j.cyto.2012.02.016

M3 - Journal article

C2 - 22445501

AN - SCOPUS:84862806229

VL - 58

SP - 384

EP - 389

JO - Cytokine

JF - Cytokine

SN - 1043-4666

IS - 3

ER -