Gene expression profiling identifies STAT3 as a novel pathway for immunomodulation by cholera toxin adjuvant.
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.
Sjöblom-Hallén
A
A
Department of Microbiology and Immunology, Institute of Biomedicine, Mucosal Immunobiology and Vaccine Center (MIVAC), Gothenburg, Sweden.
Marklund
U
U
Nerstedt
A
A
Schön
K
K
Ekman
L
L
Bergqvist
P
P
Löwenadler
B
B
Lycke
N Y
NY
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002772:Cholera Toxin / Q000494:pharmacology*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D020869:Gene Expression Profiling; D007136:Immunoglobulins / Q000096:biosynthesis / Q000235:genetics; D056747:Immunomodulation; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013154:Spleen / Q000473:pathology
D000276:Adjuvants, Immunologic; D016207:Cytokines; D007136:Immunoglobulins; D050796:STAT3 Transcription Factor; D002772:Cholera Toxin