IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis.
Sepsis is a highly lethal disorder characterized by widespread apoptosis-induced depletion of immune cells and the development of a profound immunosuppressive state. IL-7 is a potent antiapoptotic cytokine that enhances immune effector cell function and is essential for lymphocyte survival. In this study, recombinant human IL-7 (rhIL-7) efficacy and potential mechanisms of action were tested in a murine peritonitis model. Studies at two independent laboratories showed that rhIL-7 markedly improved host survival, blocked apoptosis of CD4 and CD8 T cells, restored IFN-gamma production, and improved immune effector cell recruitment to the infected site. Importantly, rhIL-7 also prevented a hallmark of sepsis (i.e., the loss of delayed-type hypersensitivity), which is an IFN-gamma- and T cell-dependent response. Mechanistically, rhIL-7 significantly increased the expression of the leukocyte adhesion markers LFA-1 and VLA-4, consistent with its ability to improve leukocyte function and trafficking to the infectious focus. rhIL-7 also increased the expression of CD8. The potent antiapoptotic effect of rhIL-7 was due to increased Bcl-2, as well as to a dramatic decrease in sepsis-induced PUMA, a heretofore unreported effect of IL-7. If additional animal studies support its efficacy in sepsis and if current clinical trials continue to confirm its safety in diverse settings, rhIL-7 should be strongly considered for clinical trials in sepsis.
Unsinger
Jacqueline
J
Department of Anesthesiology, Washington University School of Medicine, St Louis, MO 63110, USA.
McGlynn
Margaret
M
Kasten
Kevin R
KR
Hoekzema
Andrew S
AS
Watanabe
Eizo
E
Muenzer
Jared T
JT
McDonough
Jacquelyn S
JS
Tschoep
Johannes
J
Ferguson
Thomas A
TA
McDunn
Jonathan E
JE
Morre
Michel
M
Hildeman
David A
DA
Caldwell
Charles C
CC
Hotchkiss
Richard S
RS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000188:drug therapy / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D020381:Interleukin-17; D011994:Recombinant Proteins