Cutting Edge: STAT Activation By IL-19, IL-20 and mda-7 Through IL-20 Receptor Complexes of Two Types

Abstract

IL-10-related cytokines include IL-20 and IL-22, which induce, respectively, keratinocyte proliferation and acute phase production by hepatocytes, as well as IL-19, melanoma differentiation-associated gene 7, and AK155, three cytokines for which no activity nor receptor complex has been described thus far. Here, we show that mda-7 and IL-19 bind to the previously described IL-20R complex, composed by cytokine receptor family 2–8/IL-20Rα and DIRS1/IL-20Rβ (type I IL-20R). In addition, mda-7 and IL-20, but not IL-19, bind to another receptor complex, composed by IL-22R and DIRS1/IL20Rβ (type II IL-20R). In both cases, binding of the ligands results in STAT3 phosphorylation and activation of a minimal promoter including STAT-binding sites. Taken together, these results demonstrate that: 1) IL-20 induces STAT activation through IL-20R complexes of two types; 2) mda-7 and IL-20 redundantly signal through both complexes; and 3) IL-19 signals only through the type I IL-20R complex.

Conservation of the genomic structure and receptor-mediated signaling between human and rat IL-24

“…7,10 Studies using keratinocyte-specific STAT3 knockout mice have suggested that STAT3 is essential for keratinocyte migration, and plays a crucial role in skin remodeling, including hair cycle and wound healing. 30 Since STAT3 is the major STAT factor activated by IL-24, 10,12 it is tempting to hypothesize that IL-24 may play a role in epidermal functions and pathogenesis, such as wound healing and inflammation (psoriasis). 7,21 In the process of tumor development, IL-24 may also function as a cytokine to enhance cancer cell survival and growth rather than tumor suppression.…”

“…7 Expression of IL-24 was detected in spleen, thymus, 8 melanocytes, 9 ConA activated human PBMC cells, 10 LPS-treated monocytes and anti-CD3-treated T cells. 11 Two heterodimeric receptors for IL-24 have been identified, IL-20R1/IL-20R2 and IL-22R/IL-20R2, 10,12 the subunits of which belong to the class II cytokine receptor family. 13 IL-24 can bind to the IL-20R2 subunit alone, but co-expression of either IL-20R1 or IL-22R not only increases the binding affinity but also is necessary for receptor activation.…”

“…10 Once bound, IL-24 signals through the heterodimeric receptors, leading to the phosphorylation and activation of the JAK/ STAT pathway. 10,12 In contrast to the IL-10 receptor (IL-10R1/IL-10R2), which is constitutively expressed by most hemopoietic cells, 14 constitutive expression of the IL-24 receptors (IL-20R2 with at least one of the R1 chains) was not found in the immune cells tested, 11 but was detected in various nonhemopoietic tissues including lung, testis, ovary and skin, indicating a pleotropic role of IL-24 outside of the immune system. 15 Human IL-24 gene originally was known as mda-7 (melanoma differentiation associated gene-7), which was identified by subtraction hybridization as a gene whose expression was upregulated in H0-1 melanoma cells when the cells were induced to terminal differentiation by the combination of IFN-b and mezerein.…”

Association analysis of IL20RA and IL20RB genes in psoriasis

“…IL-20RB associates with IL-20RA to form IL-20RI that binds IL-19, IL20 and IL-24, and IL-20RB associates with IL-22RA1 to form IL-20-RII that binds IL-20 and IL-24. 2,13,[19][20][21] After binding of the different ligands to the receptor complexes, signals are predominantly transducted via Janus kinase-signal transducer and activation of transcription pathways. 22 IL-20-RI is mainly expressed in the skin, lung and reproductive organs as well as in various glands.…”

“…The expression of IL-20-RII seems to be more restricted with high levels detectable only in the skin. 2,13,[19][20][21] There are conflicting findings with regard to the expression of IL-20R subunits in skin lesions of psoriasis.…”