Bacterial exotoxins downregulate cathelicidin (hCAP-18/LL-37) and human β-defensin 1 (HBD-1) expression in the intestinal epithelial cells

Chakraborty, Krishnendu; Ghosh, Shubhamoy; Koley, Hemanta; Mukhopadhyay, Asish K.; Ramamurthy, Thandavarayan; Saha, Dhira Rani; Mukhopadhyay, Debashis; RoyChowdhury, S.; Hamabata, Takashi; Takeda, Yoshifumi; Das, Santasabuj

doi:10.1111/j.1462-5822.2008.01227.x

Cited by 102 publications

(78 citation statements)

References 62 publications

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“…Cells of Diverse Origins-We have recently reported that cholera toxin (CT) and LT of enterotoxigenic Escherichia coli down-regulate cathelicidin expression in NaB-differentiated intestinal ECs, possibly through ICER (43). Although the latter is known to repress transcription of genes induced by cAMP, we failed to detect induction of cathelicidin in the differentiated intestinal ECs upon stimulation of the cAMP signal transduction pathways by CT or LT. We postulated that these pathways might already be activated by NaB treatment, and this resulted in elevated cathelicidin expression in the differentiated cells.…”

Section: Camp Regulates Cathelicidin Expression In the Epithelialcontrasting

confidence: 46%

“…Although the majority of them (CREM␣, -␤, and -␥, E4BP4, and CREB2) are regulated via phosphorylation by PKA, a group of CREM family members known as ICER is stringently controlled at the transcriptional level by CREB and an autoregulatory feedback mechanism (45,46). Our previous studies have suggested that ICER may be involved in the transcriptional repression of cathelicidin (43).…”

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confidence: 99%

“…Recent reports have suggested a role for intracellular signaling molecules like ERK1/2, p38 MAPK, and transforming growth factor-␤1 kinase in NaB-mediated up-regulation of cathelicidin expression (38,40), and it is believed that histone deacetylase inhibition by NaB may also contribute to this effect (21,41). Several pathogenic microorganisms have been demonstrated to either up-or down-regulate cathelicidin in the mucosal ECs (5,22,42), and we have recently reported that bacterial exotoxins markedly suppress cathelicidin expression in the differentiated intestinal ECs in vitro and in vivo in a cAMP-dependent mechanism (43). Activation of cAMP-signaling pathways involves accumulation of cAMP second messenger inside the cells and subsequent phosphorylation of the cellular kinases (44).…”

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confidence: 99%

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cAMP Stringently Regulates Human Cathelicidin Antimicrobial Peptide Expression in the Mucosal Epithelial Cells by Activating cAMP-response Element-binding Protein, AP-1, and Inducible cAMP Early Repressor

Chakraborty

Maity

Sil

et al. 2009

Journal of Biological Chemistry

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Little is known about the regulation of the innate host defense peptide cathelicidin at the mucosal surfaces. Expression is believed to be transcriptionally regulated, and several cis-acting elements have been identified in the cathelicidin putative promoter. However, the trans-acting factors have not been clearly defined. We have recently reported that bacterial exotoxins suppress cathelicidin expression in sodium butyrate-differentiated intestinal epithelial cells (ECs), and this may be mediated through inducible cAMP early repressor. Here we have shown that cAMP-signaling pathways transcriptionally regulate cathelicidin expression in various ECs. cAMP-response elementbinding protein (CREB) and AP-1 (activator protein-1) bind to the cathelicidin putative promoter in vitro. Additionally, transcriptional complexes containing CREB, AP-1, and cathelicidin upstream regulatory sequences are formed within ECs. We have also shown that these complexes may activate cathelicidin promoter and are required for its inducible expression in ECs. This is underscored by the fact that silencing of CREB and AP-1 results in failure of ECs to up-regulate cathelicidin, and hepatitis B virus X protein may use CREB to induce cathelicidin. On the other hand, inducible cAMP early repressor competes with CREB and AP-1 for binding to the cathelicidin promoter and represses transcription, thus functioning as a counter-regulatory mechanism. Finally, both CREB and AP-1 were shown to play major roles in the regulation of cathelicidin in sodium butyrate-differentiated HT-29 cells. This is the first report of a detailed mechanistic study of inducible cathelicidin expression in the mucosal ECs. At the same time, it describes a novel immunomodulatory function of cAMP.

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Section: Camp Regulates Cathelicidin Expression In the Epithelialcontrasting

confidence: 46%

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confidence: 99%

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confidence: 99%

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cAMP Stringently Regulates Human Cathelicidin Antimicrobial Peptide Expression in the Mucosal Epithelial Cells by Activating cAMP-response Element-binding Protein, AP-1, and Inducible cAMP Early Repressor

Chakraborty

Maity

Sil

et al. 2009

Journal of Biological Chemistry

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“…31 The mechanisms involved in this regulatory process are mediated by cholera-toxin and Escherichia coli enterotoxinactivated cAMP pathways. 30 Under normal conditions the bactericidal function of hBD-1 is only weak, but, as elegantly shown recently under reductive conditions, hBD-1 is highly competent in killing Gram-positive bacteria. 32 Thus, the observed down-regulation of hBD-1 might contribute to the infiltration with these groups of bacteria in appendicitis.…”

Section: Discussionmentioning

confidence: 99%

“…A comparable down-regulation of hBD-1 was reported for infections with enterotoxin-producing gut bacteria. 30 As the richness and diversity of the bacteria in appendicitis is altered, it is tempting to speculate that enterotoxin-producing bacteria are involved in appendicitis. For infections with Cryptosporidium parvum such a suppressive effect on hBD-1 abundance was also reported.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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Appendicitis represents a common and severe gastrointestinal illness in younger individuals worldwide. The disease is characterized by an excessive inflammatory response and it is believed that bacterial overgrowth due to blockage of the appendix lumen might be involved. Despite the high incidence, only limited data on the pathophysiological changes exist; in particular, the innate immune responses involved are largely unknown. Real-time PCR analysis of tissue samples from inflamed and normal appendices demonstrated differentially regulated expression patterns of epithelial-derived antimicrobial peptides (AMP). The a-defensins human neutrophil peptides 1-3, HD5 and HD6, as well as the two b-defensins, human b-defensins (hBD)-2 and hBD-3, were up-regulated, whereas hBD-1 was down-regulated in acute appendicitis. Expression of upstream regulators of AMP expression, NOD-2 and TLRs 1, 2, 4, 5, 7, 8 and 10 was significantly increased as detected by real-time PCR. Finally, we confirmed the involvement of the pro-inflammatory cytokines IL-1b and IL-8, and detected characteristic changes in microbial community composition in appendicitis tissue specimens by 16S rDNA based detection techniques. In this study, we demonstrate a differential regulation of the innate immune system along with an altered bacterial diversity in acute appendicitis.

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Unique features of human cathelicidin LL‐37

et al. 2015

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Cathelicidins are antimicrobial peptides produced by humans and animals in response to various pathogenic microbes. This review intends to provide a brief overview of the expression, structure, properties and function of human cathelicidin LL-37 which may be a therapeutic agent against a variety of bacterial and viral diseases, cancers, and hard-to-heal wounds. Cathelicidins act as a primary defense against bacteria and other pathogens in the case of inflammation. They are able to kill bacteria and fungi, inhibit and destroy bacterial biofilms, and possess antiviral and antiparasitics properties. They can also play a role in angiogenesis, wound healing, and the regulation of apoptosis. The host defense peptide LL-37 has emerged as a novel modulator of tumor growth and metastasis in carcinogenesis of various types of cancers. LL-37 is an antimicrobial peptide able of inducing various effects. It acts as an anti- and pro- inflammatory factor. Cathelicidins are able to directly and selectively destroy membranes of various microbes and cancer cells, but they do not attack normal cells. The role of cathelicidins in cancer is double-sided. They play an important role in killing cancer cells and may provide a new possibility for the development of cancer therapeutics. However, they also can participate in carcinogenesis. Due to its activity spectrum LL-37 could be applied in pharmacotherapy. Cathelicidin peptides could serve as a template for the development of modern anti-microbial and anti-viral drugs. LL-37 is an excellent candidate to develop into therapeutics for infected wounds.

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Bacterial exotoxins downregulate cathelicidin (hCAP-18/LL-37) and human β-defensin 1 (HBD-1) expression in the intestinal epithelial cells

Cited by 102 publications

References 62 publications

cAMP Stringently Regulates Human Cathelicidin Antimicrobial Peptide Expression in the Mucosal Epithelial Cells by Activating cAMP-response Element-binding Protein, AP-1, and Inducible cAMP Early Repressor

cAMP Stringently Regulates Human Cathelicidin Antimicrobial Peptide Expression in the Mucosal Epithelial Cells by Activating cAMP-response Element-binding Protein, AP-1, and Inducible cAMP Early Repressor

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

Unique features of human cathelicidin LL‐37

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