Interleukin-12 (IL-12) is a multifunctional cytokine that plays a critical role in the regulation of immune responses. Produced primarily by antigen-presenting cells (APCs) such as dendritic cells and macrophages, IL-12 has been implicated in linking the innate and adaptive branches of the immune system, thus exerting profound effects on host defense mechanisms [1].

Structurally, IL-12 is a heterodimeric protein composed of two subunits: IL-12p35 and IL-12p40. Together, they form the biologically active IL-12p70 [2]. It is interesting to note that IL-12p40 can also pair with a different p35-like protein to form IL-23, another critical cytokine in immune regulation [3].
The principal function of IL-12 involves the activation and differentiation of T and natural killer (NK) cells. Upon binding to its specific receptor, IL-12R, which is expressed on the surface of these cells, IL-12 induces the production of interferon-gamma (IFN-γ), a potent anti-viral and immunomodulatory cytokine. Concurrently, it promotes the differentiation of naive T cells into Th1 cells, a subset of T cells that orchestrate cell-mediated immune responses[4]. This shift towards Th1 immunity, marked by high IFN-γ and IL-2 production, enhances the body’s ability to fight intracellular pathogens like viruses and certain bacteria [5].

Furthermore, IL-12 stimulates the cytotoxic activities of NK and CD8+ T cells, enhancing their ability to kill target cells [6]. It also upregulates the expression of molecules involved in antigen presentation, thereby facilitating the activation of T cells and perpetuating the immune response [7].

Recent studies have identified a role for IL-12 in the maintenance of immune homeostasis. IL-12 has been shown to induce the production of IL-10, an anti-inflammatory cytokine that curbs excessive immune responses and prevents immunopathology [8]. Moreover, the balance between IL-12 and IL-23, and by extension the balance between Th1 and Th17 responses, is crucial for immune homeostasis [9].

The importance of IL-12 in immune defense is underscored by the susceptibility of individuals with genetic defects in IL-12 or IL-12R to mycobacterial and viral infections. These individuals exhibit impaired IFN-γ production and reduced Th1 responses [10].

In the context of cancer immunotherapy, IL-12 is considered a promising candidate due to its ability to stimulate cytotoxic immune responses and its anti-angiogenic effects.

IL-12 is a pivotal cytokine in the immune system, involved in a broad array of functions ranging from the initiation and direction of adaptive immune responses, regulation of innate immunity, maintenance of immune homeostasis, and potential therapeutic applications in infectious diseases and cancer. Further research into its complex biology is likely to yield valuable insights into immune function.

References:

Trinchieri, G. (1998). Interleukin-12: A proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annual Review of Immunology, 16, 251-276.
Kobayashi, M., Fitz, L., Ryan, M., Hewick, R. M., Clark, S. C., Chan, S., Loudon, R., Sherman, F., Perussia, B., & Trinchieri, G. (1989). Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. Journal of Experimental Medicine, 170(3), 827-845.
Oppmann, B., Lesley, R., Blom, B., Timans, J. C., Xu, Y., Hunte, B., Vega, F., Yu, N., Wang, J., Singh, K., Zonin, F., Vaisberg, E., Churakova, T., Liu, M., Gorman, D., Wagner, J., Zurawski, S., Liu, Y., Abrams, J. S., Moore, K. W., Rennick, D., de Waal-Malefyt, R., Hannum, C., Bazan, J. F., & Kastelein, R. A. (2000). Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity, 13(5), 715-725.
Teng, M. W., Bowman, E. P., McElwee, J. J., Smyth, M. J., Casanova, J. L., Cooper, A. M., & Cua, D. J. (2015). IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nature Medicine, 21(7), 719-729.
Macatonia, S. E., Hsieh, C. S., Murphy, K. M., & O’Garra, A. (1993). Dendritic cells and macrophages are required for Th1 development of CD4+ T cells from alpha beta TCR transgenic mice: IL-12 substitution for macrophages to stimulate IFN-gamma production is IFN-gamma-dependent. International Immunology, 5(9), 1119-1128.
Schoenborn, J. R., & Wilson, C. B. (2007). Regulation of interferon-gamma during innate and adaptive immune responses. Advances in Immunology, 96, 41-101.
Watford, W. T., Hissong, B. D., Bream, J. H., Kanno, Y., Muul, L., & O’Shea, J. J. (2004). Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunological Reviews, 202, 139-156.
Hunter, C. A., & Kastelein, R. (2012). Interleukin-27: balancing protective and pathological immunity. Immunity, 37(6), 960-969.
Cooper, A. M., & Khader, S. A. (2007). The role of cytokines in the initiation, expansion, and control of cellular immunity to tuberculosis. Immunological Reviews, 226, 191-204.
De Jong, R., Altare, F., Haagen, I. A., Elferink, D. G., Boer, T., van Breda Vriesman, P. J., Kabel, P. J., Draaisma, J. M., van Dissel, J. T., Kroon, F. P., Casanova, J. L., & Ottenhoff, T. H. (1998). Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients. Science, 280(5368), 1435-1438.

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