IL-23 enhances the inflammatory cell response in Cryptococcus neoformans infection and induces a cytokine pattern distinct from IL-12

被引:179
作者
Kleinschek, MA
Muller, U
Brodie, SJ
Stenzel, W
Kohler, G
Blumenschein, WM
Straubinger, RK
McClanahan, T
Kastelein, RA
Alber, G [1 ]
机构
[1] Univ Leipzig, Inst Immunol, Coll Vet Med, Tierkliniken 11, D-04103 Leipzig, Germany
[2] Schering Plough Res Inst, Dept Drug Safety & Metab, Lafayette, NJ 07848 USA
[3] Univ Cologne, Fac Med, Inst Neuropathol, Cologne, Germany
[4] Univ Munster, Gerhard Domagk Inst Pathol, D-4400 Munster, Germany
[5] DNAX Res, Expt Pathol & Pharmacol, Palo Alto, CA 94304 USA
[6] DNAX Res, Discovery Res, Palo Alto, CA 94304 USA
关键词
D O I
10.4049/jimmunol.176.2.1098
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
IL-23, a heterodimeric cytokine composed of the p40 subunit of IL-12 and a novel p19 subunit, has been shown to be a key player in models of autoimmune chronic inflammation. To investigate the role of IL-23 in host resistance during chronic fungal infection, wild-type, IL-12- (IL-12p35(-/-)), IL-23- (IL-23p19(-/-)), and IL-12/IL-23- (p40-deficient) deficient mice on a C57BL/6 background were infected with Cryptococcus neoformans. Following infection, p40-deficient mice demonstrated higher mortality than IL12p35(-/-) mice. Reconstitution of p40-deficient mice with rIL-23 prolonged their survival to levels similar to IL-12p35(-/-) mice. IL-23p19(-/-) mice showed a moderately reduced survival time and delayed fungal clearance in the liver. Although IFN-gamma production was similar in wild-type and IL-23p19(-/-) mice, production of IL-17 was strongly impaired in the latter. IL-23p19(-/-) mice produced fewer hepatic granulomata relative to organ burden and showed defective recruitment of mononuclear cells to the brain. Moreover, activation of microglia cells and expression of IL-1 beta, IL-6, and MCP-1 in the brain was impaired. These results show that IL-23 complements the more dominant role of IL-12 in protection against a chronic fungal infection by an enhanced inflammatory cell response and distinct cytokine regulation.
引用
收藏
页码:1098 / 1106
页数:9
相关论文
共 43 条
[1]   Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17 [J].
Aggarwal, S ;
Ghilardi, N ;
Xie, MH ;
de Sauvage, FJ ;
Gurney, AL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (03) :1910-1914
[2]  
Aggarwal S, 2002, J LEUKOCYTE BIOL, V71, P1
[3]   IL-23 and IL-12 have overlapping, but distinct, effects on murine dendritic cells [J].
Belladonna, ML ;
Renauld, JC ;
Bianchi, R ;
Vacca, C ;
Fallarino, F ;
Orabona, C ;
Fioretti, MC ;
Grohmann, U ;
Puccetti, P .
JOURNAL OF IMMUNOLOGY, 2002, 168 (11) :5448-5454
[4]   MyD88 and TLR2, but not TLR4, are required for host defense against Cryptococcus neoformans [J].
Biondo, C ;
Midiri, A ;
Messina, L ;
Tomasello, F ;
Garufi, G ;
Catania, MR ;
Bombaci, M ;
Beninati, C ;
Teti, G ;
Mancuso, G .
EUROPEAN JOURNAL OF IMMUNOLOGY, 2005, 35 (03) :870-878
[5]   Novel IL-12 family members shed light on the orchestration of Th1 responses [J].
Brombacher, F ;
Kastelein, RA ;
Alber, G .
TRENDS IN IMMUNOLOGY, 2003, 24 (04) :207-212
[6]  
Casadevall A, 1998, CRYPTOCOCCUS NEOFORM, DOI DOI 10.1128/9781555818241
[7]   The gamma interferon receptor is required for the protective pulmonary inflammatory response to Cryptococcus neoformans [J].
Chen, GH ;
McDonald, RA ;
Wells, JC ;
Huffnagle, GB ;
Lukacs, NW ;
Toews, GB .
INFECTION AND IMMUNITY, 2005, 73 (03) :1788-1796
[8]   Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain [J].
Cua, DJ ;
Sherlock, J ;
Chen, Y ;
Murphy, CA ;
Joyce, B ;
Seymour, B ;
Lucian, L ;
To, W ;
Kwan, S ;
Churakova, T ;
Zurawski, S ;
Wiekowski, M ;
Lira, SA ;
Gorman, D ;
Kastelein, RA ;
Sedgwick, JD .
NATURE, 2003, 421 (6924) :744-748
[9]   PRODUCTION OF NATURAL-KILLER-CELL STIMULATORY FACTOR (INTERLEUKIN-12) BY PERIPHERAL-BLOOD MONONUCLEAR-CELLS [J].
DANDREA, A ;
RENGARAJU, M ;
VALIANTE, NM ;
CHEHIMI, J ;
KUBIN, M ;
ASTE, M ;
CHAN, SH ;
KOBAYASHI, M ;
YOUNG, D ;
NICKBARG, E ;
CHIZZONITE, R ;
WOLF, SF ;
TRINCHIERI, G .
JOURNAL OF EXPERIMENTAL MEDICINE, 1992, 176 (05) :1387-1398
[10]   Interleukin-12 is essential for a protective Th1 response in mice infected with Cryptococcus neoformans [J].
Decken, K ;
Köhler, G ;
Palmer-Lehmann, K ;
Wunderlin, A ;
Mattner, F ;
Magram, J ;
Gately, MK ;
Alber, G .
INFECTION AND IMMUNITY, 1998, 66 (10) :4994-5000