Introduction to IL-12 Receptor

IL-15 receptor product center

The IL-12 receptor (IL-12R), composed of interleukin 12 receptor beta 1 (IL-12Rβ1) and Interleukin 12 receptor beta 2 (IL-12Rβ2) chains, mediates signal transduction, which involves the recruitment of Janus family tyrosine kinase 2 and signal transducer and activator of transcription (STAT)4. Both of the subunits are members of the class I cytokine receptor family, and they two also have homology to gp130.

IL-12 Receptor beta1 (IL-12Rβ1) Subunit

IL-12 receptor beta1 (IL-12Rβ1) is a subunit of the interleukin 12 receptor. IL12RB1, also known as CD212 (cluster of differentiation 212) is its human gene.

The protein encoded by IL12RB1 is a type I transmembrane protein that belongs to the hemopoietin receptor superfamily. This protein binds to interleukin 12 (IL-12) with a low affinity, and is thought to be a part of IL12 receptor complex. This protein forms a disulfide-linked oligomer, which is required for its IL12 binding activity. The coexpression of this and IL12RB2 proteins was shown to lead to the formation of high-affinity IL12 binding sites and reconstitution of IL12 dependent signaling.

IL-12Rβ1 is required for high-affinity binding to the IL-12p40 subunit and it is associated with the Janus kinase (Jak) family member Tyk-2.

IL-12 Receptor beta2 (IL-12Rβ2) Subunit

IL-12 receptor beta2 (IL-12Rβ2) is a subunit of the interleukin 12 receptor. IL12RB2 is its human gene. IL12RB2 orthologs have been identified in all mammals for which complete genome data are available.

The protein encoded by IL12RB2 is a type I transmembrane protein identified as a subunit of the interleukin 12 receptor complex. The co-expression of this and IL-12Rβ1 proteins was shown to lead to the formation of high-affinity IL12 binding sites and reconstitution of IL12 dependent signaling.

IL-12Rβ2 chain mediates signal transduction via three tyrosine residues that act as a docking site for STAT4 and is associated with Jak-2. IL-12Rβ2 recognizes either the heterodimer IL-12 or the IL-12p35 subunit.

IL-12 Receptor (IL-12R) Signaling

IL-12 is a key immunoregulatory cytokine with a molecular weight of 70 kDa, composed of two covalently-linked subunits, IL-12p35 (35 kDa) and IL-12p40 (40 kDa), each of which is expressed on different chromosomes. IL-12 induces interferon-γ (IFN-γ) production and triggers CD4+ T cells to differentiate into type 1 T helper (Th1) cells. Studies have suggested that IL-12 could play a vital role in treating many diseases, such as viral and bacterial infections and cancers.

IL-12 receptor (IL-12R) and IL-12 mediates the Jak/STAT signaling pathway. Following binding of IL-12p40 and IL-12p35 to IL-12Rβ1 and IL-12Rβ2, respectively, activation of Jak kinases (Tyk-2 and Jak-2) occurs. Phosphorylated IL-12Rβ2 becomes a binding site for STAT4 proteins that are rapidly recruited to the receptor and phosphorylated on their tyrosine residues by the Jak kinases. Tyrosine phosphorylation of STAT4 proteins induces their homodimerization and translocation to the nucleus where they bind to specific sequences and regulate IFN-γ gene transcription.

IL-12 Receptor (IL-12R) Deficiency

The IL-12Rβ1 subunit is constitutively expressed, lack of expression of this gene was found to result in the immunodeficiency of patients with severe mycobacterial and Salmonella infections.

IL12Rβ2 subunit plays an important role in Th1 cell differentiation, since its absence leads to an abortive Th1 differentiation that has dysfunctional production of Th1 effector molecules. The up-regulation of this gene is found to be associated with a number of infectious diseases, such as Crohn's disease and leprosy, which is thought to contribute to the inflammatory response and host defense.

References

1. Therwa Hamza, John B. Barnett and Bingyun Li, et al. Interleukin 12 a Key Immunoregulatory Cytokine in Infection Applications. Int. J. Mol. Sci. 2010; 11:789-806.
2. Marina Afanasyeva, Yan Wang and Ziya Kaya et al. Interleukin-12 Receptor/STAT4 Signaling Is Required for the Development of Autoimmune Myocarditis in Mice by an Interferon-r–Independent Pathway. Circulation. 2001; 104:3145-3151.
3. DAVID H. PRESKY, HONG YANG and LISA J. MINETTI, et al. A functional interleukin 12 receptor complex is composed of two β-type cytokine receptor subunits. Proc. Natl. Acad. Sci. 1996; 93:14002–14007.