Mice overexpressing p40 in lungs have reduced leucocyte influx and slightly impaired resistance during tuberculosis

Interleukin (IL)-12 (p70) is a heterodimeric cytokine composed of p40 and p35, that plays a major role in the protective immune response to Mycobacterium tuberculosis. To define the role of p40 in lungs during pulmonary M. tuberculosis infection we generated transgenic (Tg) mice overexpressing p40 under control of the surfactant protein C promoter. Tg mice expressed the transgene in their lungs, yet demonstrated elevated pulmonary p40 protein levels. After infection, Tg mice displayed higher pulmonary p40 and p70 levels than wild type mice. Interferon-gamma concentrations were similar in uninfected and infected Tg and wild type mice, arguing against agonistic effects of p40. Tg mice demonstrated reduced recruitment of macrophages, lymphocytes and neutrophils to the lungs early after infection. This was accompanied by reduced pulmonary tumour necrosis factor-alpha, macrophage inflammatory protein (MIP)-2 and MIP-1alpha levels. This suggests that elevated p40 concentrations inhibited the chemotactic effects of p70 on leucocytes. Furthermore, Tg mice displayed slightly higher pulmonary mycobacterial outgrowth late in the infection than wild type mice. Taken together, we demonstrate that constitutive overexpression of p40 in lungs negatively influences IL-12-mediated leucocyte migration and protection against lung tuberculosis. This suggests a novel antagonistic role for p40 homodimers in regulating the chemotactic bioactivity of IL-12 after pulmonary mycobacterial infection.