IL-17 enhancement of the IL-6 signaling cascade in astrocytes.
Astrocytes have important physiological roles in CNS homeostasis and serve as a bridge between the CNS and immune system. IL-17 and IL-6 are important in many CNS disorders characterized by neuroinflammation. We examined the role of IL-17 on the IL-6 signaling cascade in primary astrocytes. IL-17 functioned in a synergistic manner with IL-6 to induce IL-6 expression in astrocytes. The synergistic effect involved numerous signaling pathways including NF-kappaB, JNK MAPK, and p38 MAPK. The NF-kappaB pathway inhibitor BAY-11, JNK inhibitor JNKi II, and p38 inhibitor SB203580 suppressed the synergistic effect of IL-6 and IL-17 on IL-6 expression. IL-17 synergized with IL-6 to enhance the recruitment of activated NF-kappaB p65, c-Fos, c-Jun, and the histone acetyltransferases CREB-binding protein and p300 to the IL-6 promoter in vivo to induce IL-6 transcription. This was accompanied by enhanced acetylation of histones H3 and H4 on the IL-6 promoter. Moreover, we elucidated an important role for suppressor of cytokine signaling (SOCS) 3 in IL-17 enhancement of IL-6 signaling in astrocytes. SOCS3 small interfering RNA knockdown and SOCS3 deletion in astrocytes augmented the synergistic effect of IL-6 and IL-17 due to an enhancement of activation of the NF-kappaB and MAPK pathways. These results indicate that astrocytes can serve as a target of Th17 cells and IL-17 in the CNS, and SOCS3 participates in IL-17 functions in the CNS as a negative feedback regulator.
Ma
Xiangyu
X
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Reynolds
Stephanie L
SL
Baker
Brandi J
BJ
Li
Xingang
X
Benveniste
Etty N
EN
Qin
Hongwei
H
D000818:Animals; D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D020381:Interleukin-17 / Q000502:physiology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019947:Receptors, Interleukin-6 / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
C098680:Il17a protein, mouse; D020381:Interleukin-17; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins