IL-1β and ADAM17 are central regulators of β-defensin expression in Candida esophagitis

Abstract

Candida albicans resides on epithelial surfaces as part of the physiological microflora. However, under certain conditions, it may cause life-threatening infections, including Candida sepsis. We have recently shown that human β-defensins (hBDs) hBD-2 and hBD-3 are upregulated in Candida esophagitis and that this antifungal host response is distinctly regulated by NF-κB and MAPK/activator protein-1 (AP-1) pathways. Here, we show that C. albicans induces hBD-2 through an autocrine IL-1β loop and that activation of the epidermal growth factor receptor (EGFR) by endogenous transforming growth factor-α (TGF-α) is a crucial event in the induction of hBD-3. To further dissect upstream signaling events, we investigated expression of the central sheddases for EGFR ligands ADAM10 and ADAM17 in the healthy and infected esophagus. Next, we used pharmaceutical inhibitors and small-interfering RNA-mediated knock down of ADAM10 and ADAM17 to reveal that ADAM17-induced shedding of TGF-α is a crucial step in the induction of hBD-3 expression in response to Candida infection. In conclusion, we describe for the first time an autocrine IL-1β loop responsible for the induction of hBD-2 expression and an ADAM17-TGF-α-EGFR-MAPK/AP-1 pathway leading to hBD-3 upregulation in the course of a Candida infection of the esophagus.

Epithelial Innate Immune Response to Acinetobacter baumannii Challenge

“…Here we showed that blocking of EGFR or inhibition of ADAM17 reduced the level of expression of hBD-3 induced by A. baumannii but had little effect on the level of hBD-2 induction. This observation is in line with the findings with Candida infections (33,40). Together, these results suggest that there might be a common theme in innate molecules induced in the course of microbial infection.…”

“…Several reports have indicated that EGFR activation plays a critical role in hBD-3 induction in Candida esophagitis (33,40) and Helicobacter pylori infection (41). Here we showed that blocking of EGFR or inhibition of ADAM17 reduced the level of expression of hBD-3 induced by A. baumannii but had little effect on the level of hBD-2 induction.…”

Characteristic changes in microbial community composition and expression of innate immune genes in acute appendicitis

“…In line with this, we demonstrated that mRNA abundance of IL-1b paralleled the changes in the up-regulated AMPs in the inflamed appendices. IL-1b is known to be crucial for induction of hBD-2 abundance, 14 especially in the course of fungal infections. 38 Besides IL-1b, TNF-a and IL-6, IL-8 and IL-10 were induced.…”

“…11,12 Defensins are envisaged to play significant roles in intestinal microbial homeostasis and in the primary defense against enteral and systemic infections. [11][12][13][14][15] In this study, we investigated the mRNA expression of AMPs, their potential upstream regulators and changes in bacterial diversity in acute appendicitis.…”

Interplay between Candida albicans and the Antimicrobial Peptide Armory

“…Inflammatory signaling of epithelial cells is activated further by cohabiting neutrophils, which induce upregulation of TLR4 (39), which in normal human skin may already be upregulated by contact with Gram-positive bacteria (40). TLR4 not only binds O-mannans in the C. albicans cell wall but also the defensin hBD2, which generates an autostimulatory feedback loop in epithelial cells; in addition, an autocrine IL-1␤ loop augments transcriptional responses (41). Zones of fungal infection become increasingly inflamed due to the chemoattractive activities of AMPs that recruit more lymphocytes (reviewed in reference 42).…”