The secreted form of p28 subunit of interleukin (IL)-27 inhibits biological functions of IL-27 and suppresses anti-allogeneic immune responses.
Interleukin-27 (IL-27) is a new IL-12-related heterodimeric cytokine comprising a novel p28 molecule and the Epstein-Barr-virus-induced gene 3 (EBI3) molecules. It augments initiation of T helper type 1-mediated immunity by enhancing the proliferation and cytokine production of T cells. In this study, we examined whether a secreted form of IL-27 subunits would inhibit IL-27-mediated immunological responses. COS-7 cells transduced with the mouse (m) p28 gene secreted a monomeric mp28 protein; however, those transduced with the mEBI3 gene did not detect a mEBI3 protein in the culture supernatants. The secreted mp28 prevented the IL-27-mediated signal transduction and activator of transcription 1 phosphorylation and subsequently inhibited the IL-27-mediated intercellular adhesion molecule-1 induction and interferon-gamma production in CD4(+) T cells. We generated mp28-expressing murine carcinoma Colon 26 cells and inoculated a mixture of the mp28- and mIL-27-expressing Colon 26 cells into syngeneic BALB/c mice. Simultaneous production of mp28 and mIL-27 from Colon 26 cells suppressed IL-27-mediated anti-tumour effects in the mice. We examined the p28-mediated immune suppression by inoculating mp28-expressing myoblasts into allogeneic mice. Forced production of mp28 suppressed the allogeneic cytotoxic T-lymphocyte induction and subsequently retarded the graft rejection. Furthermore, production of both mp28 and mp40, which inhibits the functions of IL-12 and IL-23, prolonged the graft survival longer than the grafts expressing either mp28 or mp40. We propose that p28 can be a regulatory subunit for IL-27-mediated cellular immune responses and a possible therapeutic agent to suppress unfavourable immune responses.
Shimozato
Osamu
O
Division of Pathology, Chiba Cancer Centre Research Institute, Nitona, Chiba, Japan.
Sato
Ayako
A
Kawamura
Kiyoko
K
Chiyo
Masako
M
Ma
Guangyu
G
Li
Quanhai
Q
Tagawa
Masatoshi
M
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D019556:COS Cells; D015815:Cell Adhesion Molecules / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005260:Female; D006085:Graft Survival / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000187:drug effects / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens; D032446:Myoblasts / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology*; D010766:Phosphorylation; D021122:Protein Subunits / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D018121:Receptors, Cytokine / Q000235:genetics / Q000276:immunology; D053707:Receptors, Interleukin-12 / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D014161:Transduction, Genetic
D015815:Cell Adhesion Molecules; C499601:Ebi3 protein, mouse; D020381:Interleukin-17; D015778:Minor Histocompatibility Antigens; D021122:Protein Subunits; D018121:Receptors, Cytokine; D053707:Receptors, Interleukin-12; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D007371:Interferon-gamma