IL-23 production by cosecretion of endogenous p19 and transgenic p40 in keratin 14/p40 transgenic mice: evidence for enhanced cutaneous immunity.
p40, the common subunit of the proinflammatory cytokines IL-12 and IL-23, is produced by resident skin cells. Whereas the in vivo effects of IL-12 are well established, little is known about the role of IL-23 in cutaneous immune responses. In this study we show that p40 transgenic (TG) mice constitutively produce IL-23 (p19/p40), but not IL-12 (p35/p40), in basal keratinocytes by cosecretion of TG p40 with endogenous p19. Repeated injections of rIL-23 in littermate (LM) mice result in an inflammatory skin disease similar to that of p40 TG mice, confirming the proinflammatory activity of IL-23. Furthermore, IL-23 secretion by p40 TG keratinocytes induces elevated numbers of Langerhans cells (LC) with a marked up-regulation of costimulatory molecules, indicating advanced maturation of keratin 14 (K14)/p40 LC when compared with LM LC. At the functional level, freshly isolated K14/p40 LC greatly exceeded LC from LM animals in their capacity to stimulate allogeneic T cell proliferation. To assess whether IL-23 regulates cutaneous immune responses in vivo, we used an allogeneic skin transplantation model. Full thickness skin grafts from K14/p40 donors (H-2(q)) transplanted across a MHC class I and class II barrier onto BALB/c (H-2(d)) recipients were rejected in a significantly accelerated fashion (mean survival time: 8.8 days) when compared with skin grafts from non-TG LM (H-2(q)) (mean survival time: 10.7 days, p < 0.01). Based on these results we propose that IL-23-induced changes of LC may be an important mechanism in directing the outcome of cutaneous immune responses.
Kopp
Tamara
T
Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, University of Vienna Medical School, Vienna International Research Cooperation Center, Vienna, Austria. tamara.kopp@ahk-wien.ac.at
Lenz
Petra
P
Bello-Fernandez
Concha
C
Kastelein
Robert A
RA
Kupper
Thomas S
TS
Stingl
Georg
G
D000818:Animals; D002452:Cell Count; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D007111:Immunity, Cellular / Q000235:genetics; D016130:Immunophenotyping; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007279:Injections, Subcutaneous; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D053762:Interleukin-12 Subunit p40; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007399:Interphase / Q000235:genetics / Q000276:immunology; D053547:Keratin-14; D007633:Keratins / Q000235:genetics*; D007801:Langerhans Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D021122:Protein Subunits / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D012867:Skin / Q000276:immunology* / Q000473:pathology; D012871:Skin Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016038:Skin Transplantation / Q000276:immunology / Q000473:pathology
C508841:Il23a protein, mouse; D053762:Interleukin-12 Subunit p40; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D053547:Keratin-14; C507446:Krt14 protein, mouse; D021122:Protein Subunits; D012333:RNA, Messenger; D018664:Interleukin-12; D007633:Keratins