Role of the Interleukin (IL)-28 Receptor Tyrosine Residues for Antiviral and Antiproliferative Activity of IL-29/Interferon-λ1

Abstract

Interferon (IFN)-1, -2, and -3 are the latest members of the class II cytokine family and were shown to have antiviral activity. Their receptor is composed of two chains, interleukin-28R/likely interleukin or cytokine or receptor 2 (IL-28R/LICR2) and IL-10R␤, and mediates the tyrosine phosphorylation of STAT1, STAT2, STAT3, and STAT5. Here, we show that activation of this receptor by IFN-1 can also inhibit cell proliferation and induce STAT4 phosphorylation, further extending functional similarities with type I IFNs. We used IL-28R/ LICR2-mutated receptors to identify the tyrosines required for STAT activation, as well as antiproliferative and antiviral activities. We found that IFN-1-induced STAT2 tyrosine phosphorylation is mediated through tyrosines 343 and 517 of the receptor, which showed some similarities with tyrosines from type I IFN receptors involved in STAT2 activation. These two tyrosines were also responsible for antiviral and antiproliferative activities of IFN-1. By contrast, STAT4 phosphorylation (and to some extent STAT3 activation) was independent from IL-28R/LICR2 tyrosine residues. Taken together, these observations extend the functional similarities between IFN-s and type I IFNs and shed some new light on the mechanisms of activation of STAT2 and STAT4 by these cytokines.The interleukin-28 receptor (IL-28R, also named LICR2 and CRF2-12) 1 is a member of the class II cytokine receptor family (CRF2) (1-3), which includes receptors for type I and type II IFNs (IFNAR1, IFNAR2, IFNGR1, and IFNGR2), tissue factor, and receptors for IL-10-related cytokines: IL-10R␣, IL-22R/ CRF2-9, IL-10R␤/CRF2-4, IL-20R␣/CRF2-8, IL-20R␤/CRF2-11, and IL-28R/LICR2 (4 -7). When IL-28R associates with IL-10R␤, it creates a high affinity binding complex for IFN-1, -2, and -3 (also called IL-29, IL-28a, and IL-28b) (2, 3). These cytokines share limited sequence similarity with type I IFNs. Like type I IFNs, they are expressed by human peripheral blood mononuclear cells and dendritic cells upon infection with viruses or stimulation with poly(I:C) (2, 3, 8).Although they use distinct receptor chains, which have no detectable homology in their intra-cytoplasmic domain, type I IFNs and IFN-s activate similar signal transduction pathways. Chimeric receptors containing the intracellular portion of IL-28R/LICR2 could mediate JAK1 (Janus kinase 1) activation, as well as tyrosine phosphorylation of STAT factors (1, 2), including STAT2, whose activation was considered to be a specific characteristic of the type I IFN response (9, 10).Most importantly, IFN-1, -2, and -3 protected several cell lines against viral infection and up-regulated major histocompatibility complex class I antigen expression (2, 3). Receptors for type I IFNs are composed of two chains, IFNAR1 and IFNAR2, in which 3 tyrosines seem to be essential to recruit STAT2: Tyr 466 in IFNAR1, and Tyr 337 and Tyr 512 in IFNAR2 (11, 12). Here, we introduced point mutations into the cytoplasmic domain of IL-28R/LICR2 to determine which tyrosines are involved in different ...

Refinement of the genetics of the host response to Salmonella infection in MOLF/Ei: regulation of type 1 IFN and TRP3 pathways by Ity2

“…Additionally, Trp53 can direct E2f2-mediated growth arrest involving the target gene Gadd45. 40 E2f2 and Gadd45 are two genes that were upregulated in the Salmonella-susceptible B6.MOLF-Ity/ Ity2.RecD congenic strain, which further supports the [41][42][43] We showed here that Trp53 expression is affected by specific Ity2A genomic context, and we speculate that its impact on resistance to Salmonella infection is explained by favoring a cell-cycle arrest state allowing the bacteria to proliferate more successfully. Therefore, we conclude that the MOLF/Ei allele at Ity2 maintains the levels of Trp53 expression within a range that allows control of bacterial growth during infection, a situation that is beneficial to the host.…”

Human interferon lambda-1 (IFN-λ1/IL-29) modulates the Th1/Th2 response

“…[8][9][10][11][12][13][14][15][16][17][18][19][20][21] However, the IFN-l ligands also induce the phosphorylation of STAT1, STAT3, STAT5 2,22 and STAT4. 23 Phosphorylation of STAT1, STAT3, STAT5 in particular, suggests more complex properties for the IFN-l ligand family; STAT3 is the signaling mechanism used by members of the IL-10 family (IL-10, IL-19, IL-20, etc. [24][25][26][27] ), whereas STAT5 is used widely by cytokines, such as IL-2, IL-3 and granulocyte-macrophage colony stimulating factor (GM-CSF).…”

Structure and function of interleukin-22 and other members of the interleukin-10 family

“…Although IFN-ks sequence similarity to IL-10 family members is even lower (*20%) than to IFN-a2 or IFN-b (*30%), these cytokines are generally considered to belong to the IL-10 family, mainly because they bind to and signal via the class II cytokine receptor IL-10R2 [4,5,96]. In this review, we will follow this somewhat broader definition of the IL-10 family, which appeared to be supported by the 3D structure of human IFN-k3 [23].…”

“…At the biological level, IFN-k1, IFN-k2, and IFN-k3 cytokines are more related to type I IFN, sharing the establishment of antiviral protection [97], antiproliferative [96], and antitumor [98][99][100] activities (reviewed in [101]). These cytokines activate the same JAK-STAT pathway, leading to the activation of STAT1/STAT2/IRF9 transcription factor complexes [4,5,96].…”

“…These cytokines activate the same JAK-STAT pathway, leading to the activation of STAT1/STAT2/IRF9 transcription factor complexes [4,5,96]. Therefore, both type I and type III IFNs are involved in the induction of a common set of genes, but differ by the duration of signaling and the tissue specificity of the expression of their respective receptors [102,103].…”