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.