Regulation of IL-8 by Irsogladine maleate is involved in abolishment of Actinobacillus actinomycetemcomitans-induced reduction of gap-junctional intercellular communication

Abstract

Our previous report has shown that Irsogladine maleate (IM) counters and obviates the reduction in gap junction intercellular communication (GJIC) and the increase in IL-8 levels, respectively, induced by outer membrane protein 29 from Actinobacillus actinomycetemcomitans (A. actinomycetemcomitans) in cultured human gingival epithelial cells (HGEC). In addition, IM suppresses the increase in the secretion of IL-8 caused by whole live A. actinomycetemcomitans. These findings implicate the modulation of IL-8 levels by IM in abolishment of the reduction of GJIC in HGEC. Tight junctions are also responsible for cell-cell communication. Zonula occludens protein-1 (ZO-1) is a major tight junction protein. To investigate the regulatory mechanism of intercellular communication mediated by IM, in the present study, we focused on the involvement of IL-8 in A. actinomycetemcomitans-induced change in GJIC and ZO-1 expression in HGEC. IM countered the A. actinomycetemcomitans-induced reduction in levels of Connexin (CX) 43, suggesting that it could abolish the A. actinomycetemcomitans-induced reduction in GJIC in HGEC. CXCR-1 is a receptor of IL-8. The simultaneous addition of A. actinomycetemcomitans and anti-CXCR-1 antibody also abrogated the repression of GJIC and CX43 expression by A. actinomycetemcomitans in HGEC, although the anti-CXCR-1 antibody was less effective than IM. IM inhibited the IL-8-induced reduction in CX43 levels and GJIC in HGEC. IM countered the A. actinomycetemcomitans-induced reduction in the expression of ZO-1, although anti-CXCR-1 antibody did not influence the decrease in ZO-1 mRNA levels caused by A. actinomycetemcomitans. Furthermore, IL-8 had little effect on the mRNA levels of ZO-1. These findings suggest that IL-8 mediates the A. actinomycetemcomitans-induced reduction of GJIC and CX43 expression in HGEC. The regulation of IL-8 levels by IM in HGEC is partially involved in abrogation of the reduction of GJIC and CX43 expression by A. actinomycetemcomitans. Furthermore, the regulatory effect of IM on the expression of CX43 and ZO-1 is different.

Integrated Epigenetics of Human Breast Cancer: Synoptic Investigation of Targeted Genes, MicroRNAs and Proteins upon Demethylation Treatment

“…This is an important finding since GJA1 is a TSG which is associated with suppression of metastasis [30]. One explanation for GJA1 down-regulation might be strong activation of IL8 in cancerous cell lines that has been also reported previously as a suppressor of GJA1 [31]. VEGFR was over-expressed in SKBR3 and HB2.…”

Irsogladine maleate abolishes the increase in interleukin‐8 levels caused by outer membrane protein 29 from Aggregatibacter (Actinobacillus) actinomycetemcomitans through the ERK pathway in human gingival epithelial cells

“…Furthermore, IM inhibits the OMP29‐induced promotion of IL‐8 expression by suppressing the phosphorylation of ERK. From the present and previous studies, IM causes the enhancement of gap junctional intercellular communication through two pathways: suppression of OMP29‐induced increase in IL‐8 through ERK and recovery of OMP29‐induced decrease in cyclic AMP levels (4,5). IM, which modulates gap junctional intercellular communication and IL‐8 expression, may be a potential therapeutic agent to prevent periodontal disease.…”

“…IM obviates the increase in IL‐8 levels and recovers the reduction of gap junctional intercellular communication in HGEC stimulated by OMP29 or A. actinomycetemcomitans (4). Furthermore, regulation of IL‐8 levels by IM causes abrogation of the reduction of gap junctional intercellular communication (5). Thus, IL‐8 is a key regulator for inflammation and the cell–cell junctional complex.…”

Irsogladine maleate inhibits Porphyromonas gingivalis‐mediated expression of toll‐like receptor 2 and interleukin‐8 in human gingival epithelial cells

“…We previously reported the effectiveness of IM in HGEC following an A. actinomycetemcomitans challenge. The IM treatment had an inhibitory effect on inflammatory cytokines and on the recovery of gap junction intercellular communication in HGEC stimulated with A. actinomycetemcomitans . The increased levels of IL‐6, IL‐8, matrix metalloproteinase‐3 and intercellular adhesion molecule 1‐1 in A. actinomycetemcomitans ‐stimulated HGEC were down‐regulated with IM via the suppression of MAP kinase (p38 and ERK signaling) .…”