IL-17A Induces Eotaxin-1/CC Chemokine Ligand 11 Expression in Human Airway Smooth Muscle Cells: Role of MAPK (Erk1/2, JNK, and p38) Pathways

Abstract

Recently, IL-17A has been shown to be expressed in higher levels in respiratory secretions from asthmatics and correlated with airway hyperresponsiveness. Although these studies raise the possibility that IL-17A may influence allergic disease, the mechanisms remain unknown. In this study, we investigated the molecular mechanisms involved in IL-17A-mediated CC chemokine (eotaxin-1/CCL11) production from human airway smooth muscle (ASM) cells. We found that incubation of human ASM cells with rIL-17A resulted in a significant increase of eotaxin-1/CCL11 release from ASM cells that was reduced by neutralizing anti-IL-17A mAb. Moreover, IL-17A significantly induced eotaxin-1/CCL11 release and mRNA expression, an effect that was abrogated with cycloheximide and actinomycin D treatment. Furthermore, transfection studies using a luciferase-driven reporter construct containing eotaxin-1/CCL11 proximal promoter showed that IL-17A induced eotaxin-1/CCL11 at the transcriptional level. IL-17A also enhanced significantly IL-1β-mediated eotaxin-1/CCL11 mRNA, protein release, and promoter activity in ASM cells. Primary human ASM cells pretreated with inhibitors of MAPK p38, p42/p44 ERK, JNK, or JAK but not PI3K, showed a significant decrease in eotaxin-1/CCL11 release upon IL-17A treatment. In addition, IL-17A mediated rapid phosphorylation of MAPK (p38, JNK, and p42/44 ERK) and STAT-3 but not STAT-6 or STAT-5 in ASM cells. Taken together, our data provide the first evidence of IL-17A-induced eotaxin-1/CCL11 expression in ASM cells via MAPK (p38, p42/p44 ERK, JNK) signaling pathways. Our results raise the possibility that IL-17A may play a role in allergic asthma by inducing eotaxin-1/CCL11 production.

IL-17A Plays a Critical Role in the Pathogenesis of Liver Fibrosis through Hepatic Stellate Cell Activation

“…Because Stat3 could be phosphorylated by activated ERK1/2, JNK, or p38 (at Ser 727 ), we further investigated which MAPK pathway may be involved. We observed that ERK1/2, p38, and JNK exhibit time-dependent phosphorylation in HSCs upon IL-17A restimulation, and their response to rmIL-17A restimulation is rapid (within 30 min), like previously observed in human airway smooth muscle cells (45,46). Furthermore, pharmacological inhibition of ERK1/2 or p38 decreased collagen and a-SMA expression in rmIL-17A-challenged or quiescent HSCs.…”

IL-17 enhances IL-1β-mediated CXCL-8 release from human airway smooth muscle cells

“…To date, only CXCL-8, eotaxin/CCL-11, and 8-isoprostane, a biomarker of oxidative stress, have been identified as inducible products from IL-17 stimulation on HASMC in vitro (34,35,42,46). Although IL-6 superinduction and protein synthesis have been observed in cotreated conditions of IL-17 and TNF-␣, IL-17 alone or in combination with IL-1␤ fails to synergize IL-6 or GM-CSF production after 24 h (16).…”

Structure–function relationships in the IL-17 receptor: Implications for signal transduction and therapy

“…The JAK-STAT pathway has also been implicated in IL-17 signaling ( [95,104,141] and R. Wu, personal communication) although activation of these factors is weak compared to Type I or II hematopoietic receptors, and could be indicative of secondary responses to IL-17-induced cytokines. Moreover, IL-17 can induce gene expression in STAT-1-deficient cells [142], and there is evidence against a role for tyrosine kinases in IL-17 gene regulation [79].…”

“…In addition, some CC chemokines are also targets of IL-17, including CCL2/MCP-1 [76,93,94], CCL11/eotaxin [95] and CCL20 [96]. ICAM-1, required for effective neutrophil recruitment to inflamed sites, is also induced by IL-17 [97].…”