Endogenous IL-10 regulates sepsis-induced thymic apoptosis and improves survival in septic IL-10 null mice.
Recent studies have shown that increased lymphocyte apoptosis contributes to sepsis-induced mortality. Furthermore, studies have demonstrated that IL-10 can suppress lymphocyte apoptosis, in part, by upregulating Bcl-2 expression and interfering with activation induced cell death. We have previously shown that intrathymic delivery of IL-10 with an adenoviral vector in wild-type mice significantly improves outcome to sepsis. Presently, we investigated the role of endogenous IL-10 expression on thymocyte apoptosis and outcome in IL-10 null mice subject to induction of generalized polymicrobial peritonitis via cecal ligation and puncture. Compared to wild-type C57BL/6 mice, IL-10 null mice demonstrated increased mortality and enhanced lymphocyte apoptosis. Intrathymic injection with an adenoviral vector expressing human IL-10 prior to cecal ligation and puncture in IL-10 null mice significantly improved outcome and decreased thymic caspase-3 activity. Furthermore, plasma concentrations of IL-6 were also significantly reduced in IL-10 null mice treated with the IL-10 expressing adenovirus. In contrast, injection of a control adenovirus did not improve outcome in IL-10 null mice, nor was caspase-3 activity reduced. Thus, local thymic expression of IL-10 not only improves outcome but also reduces local tissue apoptosis and caspase-3 activity, and appears to attenuate the systemic proinflammatory cytokine response.
Tschoeke
S K
SK
Department of Trauma and Reconstructive Surgery, Charité - University Hospitals Berlin, Campus Benjamin Franklin, Berlin, Germany. sven-kevin.tschoeke@charite.de
Oberholzer
C
C
LaFace
D
D
Hutchins
B
B
Moldawer
L L
LL
Oberholzer
A
A
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D053148:Caspase 3 / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018805:Sepsis / Q000276:immunology / Q000628:therapy*; D013950:Thymus Gland / Q000276:immunology*
C508609:IL10 protein, human; D015850:Interleukin-6; D016753:Interleukin-10; C505409:Casp3 protein, mouse; D053148:Caspase 3