Abstract
Interleukin-12 family cytokines have emerged as critical regulators of immunity with some members (IL-12, IL-23) associated with disease pathogenesis while others (IL-27, IL-35) mitigate autoimmune diseases. Each IL-12 family member is comprised of an α and a β chain, and chain-sharing is a key feature. Although four bona fide members have thus far been described, promiscuous chain-pairing between alpha (IL-23p19, IL-27p28, IL-12/IL-35p35) and beta (IL-12/IL-23p40, IL-27/IL-35Ebi3) subunits, predicts six possible heterodimeric IL-12 family cytokines. Here, we describe a new IL-12 member composed of IL-23p19 and Ebi3 heterodimer (IL-39) that is secreted by LPS-stimulated B cells and GL7(+) activated B cells of lupus-like mice. We further show that IL-39 mediates inflammatory responses through activation of STAT1/STAT3 in lupus-like mice. Taken together, our results show that IL-39 might contribute to immunopathogenic mechanisms of systemic lupus erythematosus, and could be used as a possible target for its treatment.
Keywords:
Autoimmunity ⋅ IL-12 ⋅ IL-23p19 ⋅ IL-27/IL-35Ebi3 ⋅ IL-39 ⋅ Inflammation ⋅ Systemic lupus erythematosus.
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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B-Lymphocytes / immunology
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B-Lymphocytes / metabolism
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Disease Models, Animal
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Female
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Gene Expression
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Immunophenotyping
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Inflammation / etiology
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Inflammation / metabolism
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Inflammation / pathology
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Interleukin-23 Subunit p19 / chemistry
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Interleukin-23 Subunit p19 / genetics
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Interleukin-23 Subunit p19 / metabolism*
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Lupus Erythematosus, Systemic / etiology*
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Lupus Erythematosus, Systemic / metabolism*
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Lupus Erythematosus, Systemic / pathology
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Lymphocyte Activation / immunology
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Mice
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Mice, Inbred MRL lpr
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Minor Histocompatibility Antigens / chemistry
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Minor Histocompatibility Antigens / genetics
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Minor Histocompatibility Antigens / metabolism*
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Protein Multimerization
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Receptors, Cytokine / chemistry
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Receptors, Cytokine / genetics
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Receptors, Cytokine / metabolism*
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Receptors, Interleukin / metabolism
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STAT1 Transcription Factor / metabolism
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STAT3 Transcription Factor / metabolism
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Signal Transduction
Substances
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Ebi3 protein, mouse
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Interleukin-23 Subunit p19
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Minor Histocompatibility Antigens
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Receptors, Cytokine
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Receptors, Interleukin
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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interleukin-23 receptor, mouse