Cytokines are usually grouped into families, which are based on amino acid homology and structural characteristics. The IL-12 family members are unique, in that they form heterodimers comprised of α-subunits and β-subunits [
1]. IL-12 was the first member of this family to be discovered, and along with other family members, IL-23 and IL-27, they are predominantly secreted by activated antigen presenting cells [
1]. IL-12 has a central role in polarization and promotion of type I immune responses which are characterized by preferential release of interferon gamma [
1]. IL-23 induces IL-17 from a range of conventional and non-conventional lymphocytes (the IL-23/IL-17 axis) [
2]. While IL-27 shows immune activating activity, the overall (albeit context specific) effect of IL-27 seems to be regulatory in a range of disease models [
3]. As recently published [
4], the property of IL-27 to act on co-inhibitory receptor regulation seems important. The most recent ‘fully recognized’ member of the family in humans is IL-35. IL-35 is secreted by Tregs and also activated B cells, and has immunosuppressive functions [
5,
6]. IL-12 family cytokines have an essential function in a wide range of physiologic responses in particular pathogen defense and protection of the intestinal mucosa and elicit functions via phosphorylation of members of the signal transducer and activator of transcription (STAT) family of transcription factors [
1]. As evidenced by the success of IL-12 family-related biologics (ustekinumab, guselkumab, and risankizumab) but also by described pathologies for loss of function mutations of IL-12 cytokine receptors such as Mendelian susceptibility to mycobacterial diseases (MSMD) [
7], IL-12 family cytokines are heavily implicated in pathogen defense but also inflammatory disease. IL-23 has been shown to be a key orchestrator of the psoriatic disease spectrum and therapeutic targeting has proved successful in this disease [
2,
8].
Recently, a new IL-12 family member was discovered in mice, IL-39. The IL-39 heterodimer consists of IL-23p19 (shared with IL-23) and EBI3 (shared with IL-27 and IL-35). Murine IL-39 is secreted by activated B cells, and activates neutrophils and was shown to mediate inflammation in lupus like mice [
9,
10]. Ustekinumab, originally thought to impact on IL-12p40, is now thought to show its disease modifying activity by IL-23 (IL-12p40 + IL-23p19) inhibition. Recent data from several clinical trials as well as real-life clinical observations strongly suggest that IL-23p19 blockers such as risankizumab and guselkumab are superior to ustekinumab in psoriasis [
11]. Of course, any efficacy difference between IL-12p40 blockers and IL-23p19 blockers could also be attributed to blocking of the IL-23p19 chain of IL-39. Thus, confirmation of IL-39 in humans is of great interest. Human IL-39 has not yet been detected or expressed, meaning that research into the area is slow. A recent report studying IL-12 family chain pairings in human cells detected all other IL-12 family pairings, but failed to detect a EBI3 + IL-23p19 combination, raising doubts over the existence of this cytokine in man [
12]. We, thus, aimed to study the effect of a disulfide-linked IL-39 chimera protein on human cells.