The IL-27 p28 subunit binds cytokine-like factor 1 to form a cytokine regulating NK and T cell activities requiring IL-6R for signaling.
IL-27 is formed by the association of a cytokine subunit, p28, with the soluble cytokine receptor EBV-induced gene 3 (EBI3). The IL-27R comprises gp130 and WSX-1. The marked difference between EBI3(-/-) and WSX-1(-/-) mice suggests that p28 has functions independent of EBI3. We have identified an alternative secreted complex formed by p28 and the soluble cytokine receptor cytokine-like factor 1 (CLF). Like IL-27, p28/CLF is produced by dendritic cells and is biologically active on human NK cells, increasing IL-12- and IL-2-induced IFN-gamma production and activation marker expression. Experiments with Ba/F3 transfectants indicate that p28/CLF activates cells expressing IL-6Ralpha in addition to the IL-27R subunits. When tested on CD4 and CD8 T cells, p28/CLF induces IL-6Ralpha-dependent STAT1 and STAT3 phosphorylation. Furthermore, p28/CLF inhibits CD4 T cell proliferation and induces IL-17 and IL-10 secretion. These results indicate that p28/CLF may participate in the regulation of NK and T cell functions by dendritic cells. The p28/CLF complex engages IL-6R and may therefore be useful for therapeutic applications targeting cells expressing this receptor. Blocking IL-6R using humanized mAbs such as tocilizumab has been shown to be beneficial in pathologies like rheumatoid arthritis and juvenile idiopathic arthritis. The identification of a new IL-6R ligand is therefore important for a complete understanding of the mechanism of action of this emerging class of immunosuppressors.
Crabé
Sandrine
S
Département de Pharmacologie, Université de Montréal, Montreal, Canada.
Guay-Giroux
Angélique
A
Tormo
Aurélie Jeanne
AJ
Duluc
Dorothée
D
Lissilaa
Rami
R
Guilhot
Florence
F
Mavoungou-Bigouagou
Ulrick
U
Lefouili
Fouad
F
Cognet
Isabelle
I
Ferlin
Walter
W
Elson
Greg
G
Jeannin
Pascale
P
Gauchat
Jean-François
JF
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D005982:Glutathione Transferase / Q000096:biosynthesis; D006801:Humans; D007378:Interleukins / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding / Q000276:immunology; D021122:Protein Subunits / Q000378:metabolism* / Q000502:physiology; D018121:Receptors, Cytokine / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D019947:Receptors, Interleukin-6 / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D002352:Carrier Proteins; C117709:Gsto1 protein, mouse; C486767:Il27 protein, mouse; D007378:Interleukins; C464565:MYDGF protein, human; D021122:Protein Subunits; D018121:Receptors, Cytokine; D019947:Receptors, Interleukin-6; C113554:cytokine-like factor-1; D005982:Glutathione Transferase