A novel interleukin-12 p40-related protein induced by latent Epstein-Barr virus infection in B lymphocytes

Abstract

We have isolated a cDNA encoding a novel hematopoietin receptor family member related to the p40 subunit of interleukin-12 and to the ciliary neurotrophic factor receptor, whose expression is induced in B lymphocytes by Epstein-Barr virus (EBV) infection. This gene, which we have designated EBV-induced gene 3 (EBI3), encodes a 34-kDa glycoprotein which lacks a membrane-anchoring motif and is secreted. Despite the absence of a membrane-anchoring motif and of cysteines likely to mediate covalent linkage to an integral membrane protein, EBI3 is also present on the plasma membrane of EBV-transformed B lymphocytes and of transfected cells. Most newly synthesized EBI3 is retained in the endoplasmic reticulum in an endoglycosidase H-sensitive form associated with the molecular chaperone calnexin and with a novel 60-kDa protein. EBI3 is expressed in vivo by scattered cells in interfollicular zones of tonsil tissue, by cells associated with sinusoids in perifollicular areas of spleen tissue, and at very high levels by placental syncytiotrophoblasts. EBI3 expression in vitro is induced in EBV-negative cell lines by expression of the EBV latent infection membrane protein-1 and in peripheral blood mononuclear cells by pokeweed mitogen stimulation. EBI3 maps to chromosome 19p13.2/3, near genes encoding the erythropoietin receptor and the cytokine receptor-associated kinase, Tyk2. EBI3 synthesis by trophoblasts and by EBV-transformed cells and similarities to interleukin-12 p40 are compatible with a role for EBI3 in regulating cell-mediated immune responses.

Novel IL-12 family members shed light on the orchestration of Th1 responses

“…Importantly, EBI3 is expressed in monocytes and macrophages, as is IL-12. Thus, pokeweed-mitogen activated peripheralblood mononuclear cells express EBI3 [48]. Human monocytes activated for IL-12 production also induced EBI3 gene transcription, although with slower and more prolonged kinetics than for IL-12 [2].…”

“…EBI3 was initially identified in B lymphocytes infected with EBV [48]. EBI3 is related to p40 showing 27% homology at the amino-acid sequence level [48]. Importantly, EBI3 is expressed in monocytes and macrophages, as is IL-12.…”

“…Interestingly, EBI3 is expressed throughout human pregnancy by cells of fetal origin [49] and some of the EBI3 expressed in placental trophoblasts was found to be associated with the p35 subunit of IL-12 [50]. Expression of EBI3 in EBV-infected cells as well as during pregnancy led to the suggestion that free EBI3 and/or EBI3 -p35 might counter-regulate type 1 responses [48] similar to the way by which (p40) 2 was found to antagonize the immunostimulatory action of IL-12. However, the function of EBI3 as a potential downregulator of IL-27 action remains speculative.…”

Filarial Nematode Secreted Product Es‐62 Is an Anti‐inflammatory Agent: Therapeutic Potential of Small Molecule Derivatives and Es‐62 Peptide Mimetics

“…Interestingly, it has recently emerged that IL-12 p40 and p35 subunits are components of cytokines/immunomodulators other than bioactive IL-12 p70, 51,52 for example, IL-12 p40 homodimers, IL-23 p40p19 and Epstein-Barr virus-induced gene (EBI)-3 p35. [53][54][55][56] Moreover, emerging data demonstrate that such redundancy in the IL-12/IL-23/IL-27 family, which have some overlapping and some distinct functions, extends to the role of these subunits in eliciting autoimmune disease pathogenesis with IL-12 p40 monomers being associated with systemic lupus erythematosus disease activity, 57 IL-23 p40p19 heterodimers being implicated in experimental auto-immune encephalomyelitis 58 and overexpression of IL-23 p19 resulting in multi-organ inflammation and premature death. 59 Thus, the relative kinetics and levels of induction of these individual cytokine subunits must play a key role in determining the precise phenotype of the resulting immune response and/or disease pathogenesis.…”

Gene Expression and Antiviral Activity of Interleukin-35 in Response to Influenza A Virus Infection

“…IL-35, originally named by Niedbala et al (11), consists of an IL-12/p35 and IL27/EBI3 chain. EBI3 encodes a 34-kDa glycoprotein homologous to IL-12/p40 (12). EBI3 heterodimerizes with p35, forming a hematoprotein in BJAB B lymphoma, COS7, and human placental trophoblast cells (13).…”