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Interleukin-12p40 overexpression promotes interleukin-12p70 and interleukin-23 formation but does not affect bacille Calmette-Guerin and Mycobacterium tuberculosis clearance

Olleros, Maria
Vesin, Dominique
Martinez-Soria, Eduardo
Allenbach, Cindy
Marchal, Gilles
Rahman, Jubayer
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Published in Immunology. 2007, vol. 122, no. 3, p. 350-361
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-Guerin (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.
Keywords AnimalsChemokines/biosynthesisGranuloma/immunologyImmunity, CellularInterferon-gamma/biosynthesisInterleukin-12/*biosynthesisInterleukin-12 Subunit p40/biosynthesis/*immunologyInterleukin-23/*biosynthesisLiver Diseases/immunologyMiceMice, Inbred C57BLMice, TransgenicMycobacterium bovis/*isolation & purificationMycobacterium tuberculosis/*isolation & purificationNitric Oxide Synthase Type II/metabolismSpleen/immunologyTh1 Cells/immunologyTh2 Cells/immunologyTuberculosis/*immunology/microbiology/pathologyTumor Necrosis Factor-alpha/biosynthesis
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PMID: 17623032
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