Cholera toxin induced gene expression alterations

Royaee, Atabak R.; Mendis, Chanaka; Das, Rina; Jett, Marti; Yang, David C.H.

doi:10.1016/j.molimm.2005.03.014

Cited by 14 publications

(7 citation statements)

References 22 publications

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“…27 Previous studies have documented effects by CT or E. coli labile toxin (LT) or derivatives of these holotoxins on mixed populations of human blood mononuclear cells or whole mouse lung tissues. 28,29 Our results both confirm and conflict with these reports, as will be discussed. However, a key and unique observation in this study is our finding that CT regulates STAT3 gene expression.…”

Section: Discussionsupporting

confidence: 84%

“…41 Global gene profiling showed that CT upregulated several other genes that encode proteins with diverse and critical functions, impacting on the immune system, which could also be part of the immunoenhancing functions of CT in vivo . In this list of genes, we find early-response genes, and genes involved with transcription, cell-cycle control, and membrane signaling, which is in agreement with the studies by Royaee et al 29 However, at striking variance with their study, we found less than half ( < 100 genes) as many genes to be regulated by CT exposure. This may be because we analyzed B cells exclusively, whereas Royaee et al investigated a mix of lymphocytes and monocytes.…”

Section: Articlessupporting

confidence: 92%

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Gene expression profiling identifies STAT3 as a novel pathway for immunomodulation by cholera toxin adjuvant

et al. 2010

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Earlier studies have reported on both proinflammatory and anti-inflammatory activities of cholera toxin (CT). As CT is a powerful adjuvant, we were interested in identifying genes with a possible involvement in these functions. A global gene expression analysis in mouse B cells showed that CT regulated <100 annotated genes, which encoded transcription factors, G proteins, cell-cycle regulators, and immunoregulating molecules. Interestingly, CT regulated the expression of the signal transducer and activator of transcription (STAT)3 gene and influenced the level and activation of both isoforms STAT3 alpha and STAT3 beta, in vitro in a B-cell line and in Peyer's patch (PP) B cells and in vivo in freshly isolated splenic B cells from CT-treated mice. This effect was cAMP dependent and was not seen with CTB. B cells pre-exposed to CT were significantly more susceptible to the activation of STAT3 by interleukin (IL)-6 and IL-10. This exerted a stronger inhibitory effect of IL-10 on lipopolysaccharide (LPS)-stimulated B-cell proliferation and cytokine production (IL-6). Moreover, IgG1 and IgA production induced by LPS and IL-10 were enhanced by the addition of CT to cultures of PP or splenic B cells. This is the first study to provide a molecular mechanism that can reconcile previous findings of proinflammatory and anti-inflammatory effects by CT adjuvant.

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Section: Discussionsupporting

confidence: 84%

Section: Articlessupporting

confidence: 92%

Gene expression profiling identifies STAT3 as a novel pathway for immunomodulation by cholera toxin adjuvant

et al. 2010

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“…Two other genes, the interleukin-1␤ (IL-1␤) and SOCS3 genes, which were detected as up-regulated genes during acute cholera, are known to be induced by CT. CT is known to activate IL-1␤ in both macrophages and epithelial cells (5,6). In addition, in a recent microarray study, in which a mixture of human monocytes and lymphocytes was stimulated with CT, the workers also detected up-regulation of IL-1␤ (33). The activation and increased production of IL-1␤ seem to trigger the immediate innate response and to have a potent adjuvant function in promoting a specific immune response (39).…”

Section: Resultsmentioning

confidence: 99%

Broad Up-Regulation of Innate Defense Factors during Acute Cholera

et al. 2007

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We used a whole-genome microarray screening system (Affymetrix human GeneChips covering 47,000 different transcripts) to examine the gene expression in duodenal mucosa during acute cholera. Biopsies were taken from the duodenal mucosa of seven cholera patients 2 and 30 days after the onset of diarrhea, and the gene expression patterns in the acute-and convalescent-phase samples were compared pairwise. Of about 21,000 transcripts expressed in the intestinal epithelium, 29 were defined as transcripts that were up-regulated and 33 were defined as transcripts that were down-regulated during acute cholera. The majority of the up-regulated genes characterized were found to have an established or possible role in the innate defense against infections; these genes included the LPLUNC1, LF, VCC1, TCN1, CD55, SERPINA3, MMP1, MMP3, IL1B, LCN2, SOCS3, GDF15, SLPI, CXCL13, and MUC1 genes. The results of confirmative PCR correlated well with the microarray data. An immunohistochemical analysis revealed increased expression of lactoferrin in lamina propria cells and increased expression of CD55 in epithelial cells, whereas increased expression of the SERPINA3 protein (␣ 1 -antichymotrypsin) was detected in both lamina propria and epithelial cells during acute cholera. The expression pattern of CD55 and SERPINA3 in cholera toxin (CT)-stimulated Caco-2 cells was the same as the pattern found in the intestinal mucosa during acute cholera, indicating that the activation of the CD55 and SERPINA3 genes in intestinal epithelium was induced by CT. In conclusion, during acute cholera infection, innate defense mechanisms are switched on to an extent not described previously. Both direct effects of CT on the epithelial cells and changes in the lamina propria cells contribute to this up-regulation.

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“…CT has been recognized as a potent immunomodulator, a property that largely depends on its ability to induce cAMP production, and has been extensively studied as a vaccine adjuvant (84). CT and FSK were found to induce several cytokines and chemokines, pro-as well as anti-inflammatory, in the peripheral blood mononuclear cells (85,86). Given that cathelicidin expressed at the mucosal surfaces shows multiple immunological functions (87), many of which, such as chemotaxis, angiogenesis, cytokine, and chemokine production, overlap with those of cAMP, it would be important to investigate if it may mediate immunomodulatory roles of cAMP at different mucosal sites.…”

Section: Discussionmentioning

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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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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Cholera toxin induced gene expression alterations

Cited by 14 publications

References 22 publications

Gene expression profiling identifies STAT3 as a novel pathway for immunomodulation by cholera toxin adjuvant

Gene expression profiling identifies STAT3 as a novel pathway for immunomodulation by cholera toxin adjuvant

Broad Up-Regulation of Innate Defense Factors during Acute Cholera

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

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