IL-11 protects human microvascular endothelium from alloinjury in vivo by induction of survivin expression.
IL-11 can reduce tissue injury in animal models of inflammation but the mechanism(s) is unknown. When C.B-17 SCID/beige mice bearing human skin grafts are injected i.p. with human PBMC allogeneic to the donor skin, infiltrating T cells destroy human microvessels by day 21. Intradermal injection of human IL-11 (500 ng/day) delays the time course of graft microvessel loss without reducing the extent of T cell infiltration. Protective actions of IL-11 are most pronounced on day 15. IL-11 has no effect on T cell activation marker, effector molecule, cytokine expression, or endothelial ICAM-1 expression. IL-11 up-regulates the expression of survivin, a cytoprotective protein, in graft keratinocytes and endothelial cells. Topical application of survivin antisense oligonucleotide down-regulates survivin expression in both cell types and largely abrogates the protective effect of IL-11. We conclude that in this human transplant model, IL-11 exerts a cytoprotective rather than anti-inflammatory or immunomodulatory effect mediated through induction of survivin.
Kirkiles-Smith
Nancy C
NC
Interdepartmental Program in Vascular Biology and Transplantation, Boyer Center for Molecular Medicine and Department of Pathology, Yale University School of Medicine, New Haven CT 06510, USA.
Mahboubi
Keyvan
K
Plescia
Janet
J
McNiff
Jennifer M
JM
Karras
James
J
Schechner
Jeffrey S
JS
Altieri
Dario C
DC
Pober
Jordan S
JS
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000287:Administration, Topical; D000328:Adult; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D019610:Cytoprotection / Q000235:genetics / Q000276:immunology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007271:Injections, Intradermal; D017370:Interleukin-11 / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000637:transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008833:Microcirculation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D009363:Neoplasm Proteins; D009824:Ointments; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage; D012867:Skin / Q000098:blood supply* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D016038:Skin Transplantation / Q000009:adverse effects / Q000276:immunology / Q000473:pathology*; D000077022:Survivin; D014184:Transplantation, Homologous / Q000009:adverse effects / Q000276:immunology / Q000473:pathology
D000276:Adjuvants, Immunologic; D000894:Anti-Inflammatory Agents, Non-Steroidal; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D017370:Interleukin-11; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D009824:Ointments; D016376:Oligonucleotides, Antisense; D000077022:Survivin