Inhibiting Interleukin-19 Activity Ameliorates Esophageal Squamous Cell Carcinoma Progression

Abstract

BackgroundIL-19 is expressed in esophageal squamous cell carcinoma (SCC), but its biological effect on esophageal cancer remains unclear. We determined the correlation between IL-19 expression levels and clinicopathological variables and explored the effects of IL-19 on the esophageal SCC in vivo and in vitro. Methodology/Principal FindingsWe determined the expression levels of esophageal SCC tissues from 60 patients using immunohistochemistry. We examined the effects of IL-19 on intracellular signaling, cytokines production as well as proliferation, colonization, and migration in the human esophageal SCC cell line CE81T. Monoclonal antibodies (mAbs) against IL-19 (1BB1) and its receptor IL-20R1 (51D) were used to antagonize the effects of IL-19. We injected SCID mice with CE81T cells and then treated them with anti-IL-19 mAb or control IgG every 3 days and determined tumor growth for 32 days. Of the 60 esophageal SCC patients, 36 patients (60%) were IL-19 strongly stained, which was associated with advanced tumor stage. CE81T cells expressed IL-19 and its receptors. IL-19 induced phosphorylation of STAT3, P38, JNK, ERK1/2, Akt, and NF-κB in CE81T cells. IL-19 promoted the proliferation, colonization, and migration of CE81T cells, which were antagonized by 1BB1 and 51D. IL-19 also induced expression of the transcripts of TGF-β, cyclin B1, CXCR4, and MMP-1 in CE81T cells. In CE81T tumor-bearing mice, 1BB1 reduced tumor growth and downregulated TGF-β, cyclin B1, MMP-1, and CXCR4 expression in tumors.Conclusions/SignificanceIL-19 affects the pathogenesis of esophageal cancer. IL-19 mAb (1BB1) is potentially a potent drug for esophageal cancer therapy.

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“…IL19 and IL24 [also known as melanoma differentiation-associated antigen 7 (MDA-7)] are members of the interleukin 10 (IL10) family of cytokines, which are involved in infectious and inflammatory diseases [57–61]. ESCC patients with advanced tumor stage showed increased levels of IL19 [62], and we observed higher IL19 gene expression in the NMBA-treated rat esophagus in the current study. In addition, BRBs significantly decreased levels of IL19 gene expression (Fig.…”

IL-20 and IL-20R1 antibodies protect against liver fibrosis

“…7E has previously shown specificity and neutralization activity in vitro and in vivo . 51D not only showed specificity against the extracellular domain of human (h)IL‐20R1, but also cross‐reacted with mouse (m)IL‐20R1 and rat (r)IL‐20R1 (Supporting Fig. 3).…”

Cytokine-chemokine network driven metastasis in esophageal cancer; promising avenue for targeted therapy

“…These factors mediate activation of TGF-β, cyclin B1, matrix metalloproteinase-1 and CXCR4, all related to the proliferation and metastasis of cancer cells. In vivo studies have shown that anti-IL-19 antibody can significantly inhibit the growth of EC [ 78 ].

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