title: Interleukin-12p40 overexpression promotes interleukin-12p70 and interleukin-23 formation but does not affect bacille Calmette-Guérin and Mycobacterium tuberculosis clearance.
abstract: Interleukin (IL)-12p40, a subunit of IL-12p70 and IL-23, has previously been shown to inhibit IL-12p70 activity and interferon-gamma (IFN-gamma) production. However, recent evidence has suggested that the role of IL-12p40 is more complex. To study the contribution of IL-12p40 to immune responses against mycobacterial infections, we have used transgenic (tg) mice overexpressing IL-12p40 under the control of a major histocompatibility complex-II promoter. The IL-12p40 transgene was expressed during steady state at concentrations of 129 +/- 25 ng/ml of serum and 75 +/- 13 ng per spleen, while endogenous IL-12p40 was hardly detectable in control littermates. Bacille Calmette-Guérin (BCG) infection strongly induced the expression of IL-12p40 transgene in infected organs, and IL-12p40 monomeric and dimeric forms were identified in spleen of IL-12p40 tg mice. Excessive production of IL-12p40 resulted in a 14-fold increase in IL-12p70 serum levels in tg mice versus non-transgenic mice. IL-23 was also strongly elevated in the serum and spleens of IL-12p40 tg mice through BCG infection. While IFN-gamma and tumour necrosis factor protein levels were similar in IL-12p40 tg and non-transgenic mice, Th2 type immune responses were reduced in IL-12p40 tg mice. The number of BCG granulomas and macrophage expressing inducible nitric oxide synthase were similar in IL-12p40 tg and non-transgenic mice. IL-12p40 tg mice were as resistant as non-transgenic mice to BCG and Mycobacterium tuberculosis infections as they could efficiently control bacillary growth. These data show that high amounts of IL-12p40 promotes IL-12p70 and IL-23 formation, but that does not affect T helper 1 type immune responses and granuloma function, thus leading to normal mycobacterial clearance in infected organs.
authors.affiliation: Department of Pathology and Immunology and Clinical Pathology, CMU, Faculty of Medicine, University of Geneva, 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Olleros
authors.forename: Dominique
authors.initials: D
authors.lastname: Vesin
authors.forename: Eduardo
authors.initials: E
authors.lastname: Martinez-Soria
authors.forename: Cindy
authors.initials: C
authors.lastname: Allenbach
authors.forename: Fabienne
authors.initials: F
authors.lastname: Tacchini-Cottier
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Pache
authors.forename: Gilles
authors.initials: G
authors.lastname: Marchal
authors.forename: Jubayer
authors.initials: J
authors.lastname: Rahman
authors.forename: Carmen
authors.initials: C
authors.lastname: Fernández
authors.forename: Shozo
authors.initials: S
authors.lastname: Izui
authors.forename: Irene
authors.initials: I
authors.lastname: Garcia
mesh_terms: D000818:Animals; D018925:Chemokines / Q000096:biosynthesis; D006099:Granuloma / Q000276:immunology; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis*; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis / Q000276:immunology*; D053759:Interleukin-23 / Q000096:biosynthesis*; D008107:Liver Diseases / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009163:Mycobacterium bovis / Q000302:isolation & purification*; D009169:Mycobacterium tuberculosis / Q000302:isolation & purification*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D013154:Spleen / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D018925:Chemokines; D053762:Interleukin-12 Subunit p40; D053759:Interleukin-23; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II