Structure of IL-12
Biologically active IL-12 is a disulfide-linked heterodimeric 70-kDa cytokine composed of a 35-kDa (p35) and a 40-kDa (p40) subunit. p35, a member of the IL-6 superfamily, is secreted in response to IFN gamma and agonists of TLR3, 4, or 7. However, p35 expression has been shown to be inhibited by Th2 cytokines and expressed at much lower levels than p40. Expression of p40 is regulated independently of p35. Moreover, p40 has been shown to be secreted as either a monomer or homodimer. Although each subunit alone does not possess IL-12 bioactivity, the p40 homodimer can bind to the IL-12 receptor and act as an antagonist to IL-12 p70. The receptor for this cytokine is composed of two subunits, IL-12R beta 1 and IL-12R beta 2, the latter of which is the signaling component of the receptor.
Function of IL-12
Formerly called cytotoxic lymphocyte maturation factor (CLMF) or natural killer cell stimulatory factor (NKSF), IL-12 is a pleiotropic cytokine. IL-12 is mainly produced by monocytes, macrophages, and dendritic cells in response to bacterial products such as lipopolysaccharide (LPS), intracellular pathogens, or upon interaction with activated T cells. This cytokine can induce IFN gamma production, cell proliferation, and cytotoxicity mediated by natural killer cells and T cells. Studies have established that IL-12 is essential for the differentiation, proliferation, and maintenance of T helper 1 (Th1) responses that lead to IFN gamma and IL-2 production. In turn, these cytokines promote T cell responses and macrophage activation.
Role of IL-12 in Disease
IL-12 has been shown to play a critical role in the pathogenesis of a variety of immune-related diseases. Aberrant IL-12 expression has been reported in bacterial and viral infections (e.g., Mycobacterium tuberculosis and HIV), obstructive jaundice, and septic shock. In addition, IL-12 has been associated with autoimmune and inflammatory conditions such as allograft rejection, osteoarthritis, rheumatoid arthritis, seronegative spondylarthropathy, and atherosclerosis. In addition to immune-mediated inflammatory diseases, increased IL-12 plasma levels are also detected in patients with neurological disorders such as multiple sclerosis.