IL-23 Production by Cosecretion of Endogenous p19 and Transgenic p40 in Keratin 14/p40 Transgenic Mice: Evidence for Enhanced Cutaneous Immunity

• Published in: The Journal of immunology (1950) 2003-06, Vol.170 (11), p.5438-5444
• Main Authors: Kopp, Tamara, Lenz, Petra, Bello-Fernandez, Concha, Kastelein, Robert A, Kupper, Thomas S, Stingl, Georg
• Format: Article
• Language: English
• Subjects: Animals; Cell Count; Cell Movement - genetics; Cell Movement - immunology; Cells, Cultured; Female; Graft Rejection - genetics; Graft Rejection - immunology; Immunity, Cellular - genetics; Immunophenotyping; Inflammation - genetics; Inflammation - immunology; Injections, Subcutaneous; Interleukin-12 - biosynthesis; Interleukin-12 - genetics; Interleukin-12 - metabolism; Interleukin-12 Subunit p40; Interleukin-23; Interleukin-23 Subunit p19; Interleukins - administration & dosage; Interleukins - biosynthesis; Interleukins - genetics; Interleukins - metabolism; Interphase - genetics; Interphase - immunology; Keratin-14; Keratins - genetics; Langerhans Cells - immunology; Langerhans Cells - metabolism; Langerhans Cells - pathology; Lymphocyte Activation - genetics; Lymphocyte Culture Test, Mixed; Mice; Mice, Inbred BALB C; Mice, Transgenic; Organ Culture Techniques; Protein Subunits - biosynthesis; Protein Subunits - genetics; Protein Subunits - metabolism; RNA, Messenger - biosynthesis; Skin - immunology; Skin - pathology; Skin Diseases - genetics; Skin Diseases - immunology; Skin Diseases - pathology; Skin Transplantation - immunology; Skin Transplantation - pathology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.170.11.5438

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.