Abstract
Members of the IL-6/IL-12 cytokine family are critical regulators of innate and adaptive immunity and have emerged as key players controlling inflammatory and autoimmune disorders. This cytokine family comprises of IL-12, IL-23, IL-27, and IL-35, each consisting of distinct α- and β-cytokine subunits that form heterodimers. A new member of this family, IL-39, was identified in the murine species and was shown to consist of the IL-23p19 and Epstein-Barr Virus-induced 3 (EBI3) subunits. Subsequently, it was shown that IL-39 was implicated in the immunopathogenesis of murine experimental lupus erythematosus. The existence of IL-39 in the human system has yet to be confirmed. Based on the clinical success of IL-23p19 neutralizing approaches in moderate-to-severe psoriasis, anti-IL-23p19 antibodies in the clinic may not only neutralize IL-23, but additionally IL-39, implying that IL-39 might also contribute to the pathogenesis of psoriasis. It is therefore pivotal to demonstrate IL-39 expression and to characterize its function in the human system. In this study, we provided evidence for the existence of secreted heterodimeric p19 and EBI3 complexes in supernatants originating from p19 and EBI3 transfected HEK293FT cells. We attempted to detect IL-39 expression from stimulated human primary B cells, human keratinocytes and in vitro polarized human macrophages. Whereas, the expression of p19 and EBI3 mRNA was elevated, we failed to detect p19 and EBI3 heterodimers. Functional assays were conducted with conditioned media containing human IL-39 or with a human recombinant IL-39 Fc protein. Immune cells targeted by IL-39 in mouse, such as neutrophils and PBMCs, did not respond to human IL-39 stimulation and IL-39 failed to activate STAT3 in a reporter cell line. These results suggest that, while the secretion of p19/EBI3 complexes can be forced in human cells, it is secreted below the lower quantity of detection or it has no functional role.
Highlights
Members of the IL-6/IL-12 cytokine family consist of IL-12, IL-23, IL-27 and IL-35 and have unique structure properties in that they form heterodimers comprising distinct α- and β-subunits
Human IL-39 exists as a secreted IL-23p19/EpsteinBarr Virus-induced 3 (EBI3) heterodimeric cytokine
In order to test whether the human p19/EBI3 heterodimeric complex can form, we transiently co-transfected HEK293FT cells with plasmid constructs encoding for the two subunits
Summary
Members of the IL-6/IL-12 cytokine family consist of IL-12, IL-23, IL-27 and IL-35 and have unique structure properties in that they form heterodimers comprising distinct α- and β-subunits. No evidence for expression and function of IL-39 in human immune cells at time of studies. This does not alter adherence to PLOS ONE policies on sharing data and materials. A new member of the IL-6/IL-12 family, termed IL-39, was recently discovered in mice It is composed of a heterodimeric complex consisting of the p19 α (shared with IL-23) and of the EBI3 β (shared with IL-27/IL-35) subunits [11]. Because of the potential pro-inflammatory and pathogenic property of IL-39, we attempted to clarify whether IL-39 exists and whether it has a biological function in the human system
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