Interleukin-12p40 variant form reduces Interleukin-12p80 secretion

IL-12 is a key cytokine for the promotion of CD4(+) T cells differentiation to type 1 helper T cells. IL-12 is a heterodimer (IL-12p70) consisting of p40 and p35 subunits, and is mainly secreted from activated antigen presenting cells, such as macrophages and dendritic cells (DCs). In this study, we found that activated mouse bone marrow-derived DCs (BMDCs) produced a p40 splice variant form mRNA in addition to the conventional p40 mRNA. This p40 variant mRNA was produced by alternative splicing in exon 5, and possessed a premature stop codon. As a result, the p40 variant protein contained 157 amino acids of the N-terminal part of p40 and an additional 10 novel amino acids. When the p40 variant was expressed in HEK-293T cells, it was not secreted from the cells. To investigate the function of the p40 variant, it was co-expressed with p40 and/or p35. The p40 variant did not affect the secretion of IL-12p40 or IL-12p70, or the function of the secreted p70. In contrast, the secretion of IL-12p80, a homodimeric IL-12 with two p40 subunits, was significantly decreased when the p40 variant was expressed. This new splicing variant p40 may act to fine-tune the function of IL-12p80.