Histone-deacetylase inhibitors induce the cathelicidin LL-37 in gastrointestinal cells

Schauber, Jürgen; Iffland, Konrad; Frisch, Susanne; Kudlich, Theodor; Schmausser, B; Eck, Matthias; Menzel, Thomas; Gostner, Andrea; Lührs, Hardi; Scheppach, Wolfgang

doi:10.1016/j.molimm.2004.05.005

Cited by 99 publications

(80 citation statements)

References 40 publications

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“…Several studies have described NaB as a potent inducer of cathelicidin in various epithelial cells (21,38). We, however, observed little effect of NaB on cathelicidin expression levels in the HT-29 and A549 cells at the time points when they exhibited the highest induction by cAMP.…”

Section: Discussioncontrasting

confidence: 64%

“…Although researchers have described several NaB-responsive elements in the cathelicidin upstream regulatory region, efforts to identify specific trans-acting factors remain largely elusive (39). 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).…”

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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: Discussioncontrasting

confidence: 64%

mentioning

confidence: 99%

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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“…The underlying mechanisms of cathelicidin expression are only beginning to be understood (24), but recent studies have revealed that cathelicidin expression is regulated via the MAPK signaling pathway. Interestingly, it has been shown that the inhibition of p38 kinase pathway significantly decreased cathelicidin gene expression in human keratinocytes (23).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, it has been shown that the inhibition of p38 kinase pathway significantly decreased cathelicidin gene expression in human keratinocytes (23). However, Schauber et al demonstrated that inhibition of the ERK1/2 pathway but not the p38 MAPK pathway blocked sodium butyrate-induced cathelicidin gene expression in colonic, gastric, and hepatic cells (24). In contrast, our present data show that M. bovis BCG-stimulated LL-37 production can be regulated by both the ERK1/2 and p38 MAPK signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Expression and Secretion of Cathelicidin LL-37 in Human Epithelial Cells after Infection byMycobacterium bovisBacillus Calmette-Guérin

Méndez-Samperio¹,

Miranda²,

Trejo³

2008

Clin Vaccine Immunol

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“…Sodium butyrate has histone deacetylase (HDAC) inhibitory activity (43), and to determine whether sodium butyrate's effects on the cxcl13 promoter were due to this effect, we compared its ability to modulate the cxcl13 promoter after pretreatment of cells…”

Section: Resultsmentioning

confidence: 99%

Macaque Paneth Cells Express Lymphoid Chemokine CXCL13 and Other Antimicrobial Peptides Not Previously Described as Expressed in Intestinal Crypts

Lucero

Junecko

Klamar

et al. 2013

Clin Vaccine Immunol

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dCXCL13 is a constitutively expressed chemokine that controls migration of immune cells to lymphoid follicles. Previously, we found CXCL13 mRNA levels increased in rhesus macaque spleen tissues during AIDS. This led us to examine the levels and locations of CXCL13 by detailed in situ methods in cynomolgus macaque lymphoid and intestinal tissues. Our results revealed that there were distinct localization patterns of CXCL13 mRNA compared to protein in germinal centers. These patterns shifted during the course of simian immunodeficiency virus (SIV) infection, with increased mRNA expression within and around follicles during AIDS compared to uninfected or acutely infected animals. Unexpectedly, CXCL13 expression was also found in abundance in Paneth cells in crypts throughout the small intestine. Therefore, we expanded our analyses to include chemokines and antimicrobial peptides (AMPs) not previously demonstrated to be expressed by Paneth cells in intestinal tissues. We examined the expression patterns of multiple chemokines, including CCL25, as well as ␣-defensin 6 (DEFA6), ␤-defensin 2 (BDEF2), rhesus -defensin 1 (RTD-1), and Reg3␥ in situ in intestinal tissues. Of the 10 chemokines examined, CXCL13 was unique in its expression by Paneth cells. BDEF2, RTD-1, and Reg3␥ were also expressed by Paneth cells. BDEF2 and RTD-1 previously have not been shown to be expressed by Paneth cells. These findings expand our understanding of mucosal immunology, innate antimicrobial defenses, homeostatic chemokine function, and host protective mechanisms against microbial translocation.

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Histone-deacetylase inhibitors induce the cathelicidin LL-37 in gastrointestinal cells

Cited by 99 publications

References 40 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

Expression and Secretion of Cathelicidin LL-37 in Human Epithelial Cells after Infection byMycobacterium bovisBacillus Calmette-Guérin

Macaque Paneth Cells Express Lymphoid Chemokine CXCL13 and Other Antimicrobial Peptides Not Previously Described as Expressed in Intestinal Crypts

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