Interleukin (IL)-39 [IL-23p19/Epstein–Barr virus-induced 3 (Ebi3)] induces differentiation/expansion of neutrophils in lupus-prone mice

Abstract

Interleukin (IL)-12 family cytokines play critical roles in autoimmune diseases. Our previous study has shown that IL-23p19 and Epstein-Barr virus-induced 3 (Ebi3) form a new IL-12 family heterodimer, IL-23p19/Ebi3, termed IL-39, and knock-down of p19 or Ebi3 reduced diseases by transferred GL7 B cells in lupus-prone mice. In the present study, we explore further the possible effect of IL-39 on murine lupus. We found that IL-39 in vitro and in vivo induces differentiation and/or expansion of neutrophils. GL7 B cells up-regulated neutrophils by secreting IL-39, whereas IL-39-deficient GL7 B cells lost the capacity to up-regulate neutrophils in lupus-prone mice and homozygous CD19 (CD19-deficient) mice. Finally, we found that IL-39-induced neutrophils had a positive feedback on IL-39 expression in activated B cells by secreting B cell activation factor (BAFF). Taken together, our results suggest that IL-39 induces differentiation and/or expansion of neutrophils in lupus-prone mice.

Cytokines in the pathogenesis of rheumatoid arthritis: new players and therapeutic targets

“…The signal is transduced via cytoplasmic myeloid differentiation primary response protein 88 (MyD88) and IL-1R associated kinase 4 (IRAK4), ending up in the activation of transcriptions factors like NF-kB or MAPK [7]. IL-33 (IL-1F11) was identified in high ↑ vs HD, OA and PsA [70][71][72][73] ↑ in RA-ILD [71] ↑ in erosive RA [71] Lower baseline levels predict good response to anti-TNF-α agents [74,75] Detectable levels at baseline predict response to RTX [77] Detectable levels at baseline predict atherosclerotic plaque progression [76] na ↑ vs OA [26] = vs OA [72] Lower baseline levels predict good response to anti-TNF-α agents [74,75] IL-36 IL-36 is upregulated in CIA, CAIA and AIA [122,123] IL-36 blockade does not affect arthritis [122,123] ↑ vs HD [133] n a ↑ vs OA [126] IL-37 Systemic and intra-articular administration of recombinant IL-37 inhibits the development of synovitis in CIA and AIA [146,147] ↑ vs HD [133] ↑ vs HD and OA [147][148][149][150] ↑ in FR + and anti-CCP + patients vs seronegative [150] ↑ in active vs inactive RA [149] ↑ in erosive RA [150] ↑ [150] ↑ [147] IL-38 IL-38 KO mice display more severe AIA [131] IL-38 overexpression attenuates CIA and STIA [132] = vs HD and OA [131] ↑ vs HD [133] na ↑ vs OA [131] Other IL-32 IL-32 administration worsens CIA …”

“…For the sake of completeness, it should be mentioned that very recently another family member, IL-39, has been described. IL-39 is composed of IL-23p19 and EBI3 heterodimer, is secreted by activated B lymphocytes and seems to play a pathogenic role in mouse models of systemic lupus erythematosus [70,71], but no data on RA or other diseases are available so far. These cytokines transduce the signal through unique pairings of 5 receptor chains: IL-12Rβ1, IL-12Rβ2, IL-23R, IL-27Rα (or WSX-1) and gp130.…”

The toll-like receptor 3 pathway in homeostasis, responses to injury and wound repair

“…This suggests that IL-23p19 and EBI3 may function as a novel IL-12 family cytokine. Indeed, these two subunits were very recently reported to form IL-39, which was shown to promote neutrophil expansion in lupus-prone mice [64,65]. Therefore, IL-39 may play a role downstream of TLR3 in wound healing responses in the skin by promoting neutrophil-mediated responses at the site of injury.…”

Innate Immunity in Coronary Disease. The Role of Interleukin-12 Cytokine Family in Atherosclerosis

“…IL-35 is a suppressive cytokine inhibiting the development of Th17 cells, the proliferation of effector T-cells 25 , and inhibiting effector T-cell's responses 8,24 in an IL-10 dependent way 26 . Alternatively, IL-39 was shown to induce differentiation and/or expansion of neutrophils 27 ( Fig. 1).…”