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A DNA sequence encoding the human IL-12 protein sequence (containing the signal peptide and the mature IL-12 alpha chain sequence, and the signal peptide and the mature IL-12 beta chain sequence) was expressed in modified human 293 cells.

Human interleukin 12 (IL-12, IL12) is a pro-inflammatory cytokine that consists of a heterodimer comprising two disulfide-linked subunits, the alpha chain (the p35 subunit, IL-12A) and the beta chain (the p40 subunit, IL-12B). IL-12A is synthesized as a 219 amino acid peptide including a 22 amino acid signal sequence and has 2 potential N-linked glycosylation sites and a theoretical molecular mass of approximately 22 kDa. IL-12B is synthesized as a 328 amino acid peptide including a 22 amino acid signal sequence and has two potential N-linked glycosylation sites and a theoretical molecular mass of 35 kDa. Expression of the alpha chain and beta chain is regulated independently as the genes for the different subunits are located on different chromosomes. The majority of cell types have the ability to express the alpha chain. However, beta chain expression is restricted to dendritic cells, phagocytic cells and cells of the monocyte/macrophage lineage and B cells. It is these cells that predominantly express functional IL-12. IL-12 production is induced by both innate and adaptive immune responses. Induction via the innate immune response involves pathogen products such as bacterial LPS and various cell wall components, CpG nucleic acids and double stranded RNA. Additionally, the process of phagocytosis of bacteria also induces IL-12. The induction of IL-12 expression via the adaptive immune response involves the interaction of antigen presenting cells (APC) with TH cells, through CD40-CD40L interaction. Additionally, cross-linking of MHC II by TCR or CD4 induces IL-12. Importantly, at least two different signals are required for the induction of IL-12: CD40 ligation and a co-stimulatory cytokine, a bacterial product and IFN gamma, or CD40L and bacterial product. IL-12 plays a crucial role in regulating both cell mediated and innate immunity. Specifically, it is the major cytokine responsible for inducing T helper 1 (TH1) cell, cytotoxic T-cell (CTL) and natural killer (NK) cell immune responses. Furthermore, IL-12 acts on T cells, and NK cells, stimulating proliferation and inducing the production of interferon-gamma (IFN-gamma). IL-12 also promotes the proliferation and differentiation of naive CD4+ T cells into TH1 cells that produce IFN-gamma, which in turn enhances IL-12 production in dendritic cells and phagocytes resulting in a strong positive feedback mechanism leading to a powerful cell mediated immune response. For a review on the biology of IL-12 please refer to Gately et. al., (1998) Ann Rev Immunol 16: 495-521.