Inflammatory skin disease in K14/p40 transgenic mice: Evidence for interleukin-12-like activities of p40

The proinflammatory cytokine interleukin-12, a p35/ p40 heterodimer, is pro duced by resident cells in skin and has been implicated as a pathogenetic f actor in T-cell-mediated skin diseases. Secretion of heterodimeric interleu kin-12 is always accompanied by production of P40 monomer and p40/p40 homod imer. To investigate the possible in vivo role of p40 per se, we generated mice that constitutively express monomeric and homodimeric p40 in basal ker atinocytes. These mice spontaneously developed an eczematous skin disease t hat was characterized by hyperkeratosis, focal epidermal spongiosis, and a mixed inflammatory infiltrate composed of T cells (CD4(+)), macrophages, eo sinophils, mast cells, and few neutrophils. Fluorescence-activated cell sor ter analysis of transgenic epidermal cell suspensions revealed induction of major histocompatibility complex class II molecules on keratinocytes and a 2-3-fold increase in the content of Langerhans cells. Cytokines produced b y these activated epidermal cells include interleukin-la and tumor necrosis factor alpha. The skin disease in K14/p40 mice was similar to that of litt ermate mice that received injections of interleukin-12, suggesting overlapp ing in vivo functional properties. As induction of interferon-gamma is a ma jor function of interleukin-12, we tested the in vitro ability of transgeni c p40 to induce interferon-gamma. In contrast to interleukin-12, transgenic p40 did not stimulate interferon-gamma secretion by cultured splenocytes. We conclude that transgenic p40 and interleukin-12 are equally capable of i nitiating cutaneous inflammation. Despite these in vivo similarities, there is a clear functional difference between interleukin-12 and transgenic p40 in vitro, suggesting that interferon-gamma is not a major factor contribut ing to interleukin-12-like activities of transgenic p40.