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Elevated interleukin‐27 levels in human neonatal macrophages regulate indoleamine dioxygenase in a STAT ‐1 and STAT ‐3‐dependent manner
Author(s) -
Jung JooYong,
Gleave Parson Madeline,
Kraft Jennifer D.,
Lyda Logan,
Kobe Brianna,
Davis Celestia,
Robinson Jembber,
Peña Maria Marjorette O.,
Robinson Cory M.
Publication year - 2016
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12625
Subject(s) - stat , cytokine , biology , stat4 , indoleamine 2,3 dioxygenase , immune system , stat protein , interleukin 10 , immunology , interleukin , endogeny , stat6 , signal transduction , interleukin 4 , microbiology and biotechnology , endocrinology , stat3 , biochemistry , tryptophan , amino acid
Summary Microbial infections are a major cause of infant mortality as a result of limitations in immune defences. Interleukin‐27 ( IL ‐27) is a heterodimeric cytokine produced primarily by leucocytes and is immunosuppressive toward lymphocytes and leucocytes. Our laboratory demonstrated that human neonatal macrophages express IL ‐27 more abundantly than adult macrophages. Similarly in mice, IL ‐27 expression is elevated early in life and maintained through infancy. To determine IL ‐27‐regulated mechanisms that may limit immunity, we evaluated the expression of a number of genes in response to this cytokine in primary human neonatal macrophages. Indoleamine 2,3‐dioxygenase ( IDO ) gene expression was increased dose‐responsively by IL ‐27. We have previously demonstrated inhibition of T‐cell proliferation and cytokine production by neonatal macrophage‐generated IL ‐27, and IDO is often implicated in this negative regulation. An increase in IDO protein was demonstrated by immunofluorescence microscopy and was consistent with increased enzyme activity following treatment with IL ‐27. Inclusion of a soluble receptor to neutralize endogenous IL ‐27, decreased IDO expression and activity compared with untreated macrophages. In response to IL ‐27, neonatal macrophages phosphorylate signal transdcuer and activator of transcription 1 ( STAT ‐1) and STAT ‐3. Both transcription factors are recruited to the IDO regulatory region. STAT ‐3 dominates during steady‐state regulation by lower levels of endogenous IL ‐27 production. A shift to enhanced STAT ‐1 recruitment occurs during increased levels of exogenously supplied IL ‐27. These data suggest an interesting interplay of STAT ‐1 and STAT ‐3 to regulate IDO activity and immunosuppression in response to different levels of IL ‐27 in the microenvironment of the immune response that may further our understanding of this interesting cytokine.