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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.
AuthorsMaria L Olleros, Dominique Vesin, Eduardo Martinez-Soria, Cindy Allenbach, Fabienne Tacchini-Cottier, Jean-Claude Pache, Gilles Marchal, Jubayer Rahman, Carmen Fernández, Shozo Izui, Irene Garcia
JournalImmunology (Immunology) Vol. 122 Issue 3 Pg. 350-61 (Nov 2007) ISSN: 0019-2805 [Print] England
PMID17623032 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Chemokines
  • Interleukin-12 Subunit p40
  • Interleukin-23
  • Tumor Necrosis Factor-alpha
  • Interleukin-12
  • Interferon-gamma
  • Nitric Oxide Synthase Type II
Topics
  • Animals
  • Chemokines (biosynthesis)
  • Granuloma (immunology)
  • Immunity, Cellular
  • Interferon-gamma (biosynthesis)
  • Interleukin-12 (biosynthesis)
  • Interleukin-12 Subunit p40 (biosynthesis, immunology)
  • Interleukin-23 (biosynthesis)
  • Liver Diseases (immunology)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mycobacterium bovis (isolation & purification)
  • Mycobacterium tuberculosis (isolation & purification)
  • Nitric Oxide Synthase Type II (metabolism)
  • Spleen (immunology)
  • Th1 Cells (immunology)
  • Th2 Cells (immunology)
  • Tuberculosis (immunology, microbiology, pathology)
  • Tumor Necrosis Factor-alpha (biosynthesis)

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