Pulmonary Immune Response And Vascular Remodeling In Important Transcriptional Regulatory Mechanism Research

Chapter1Adenosine signaling inhibits CIITA-mediated MHC IItransactivation in lung fibroblast cellsEfficient antigen presentation by major histocompartibility complex (MHC)molecules represents a critical process in adaptive immunity. Class II transactivator(CIITA) is considered the master regulator of MHC II transcription. Previously wehave shown that CIITA expression is up-regulated in smooth muscle cells deficientin A2b adenosine receptor. Here we report that treatment with the adenosine receptoragonist NECA attenuated MHC II transcription in lung fibroblast cells as a result ofCIITA repression. Further analysis revealed that NECA preferentially abrogatedCIITA transcription through promoter III and promoter IV. Blockade with a selectiveA2b receptor antagonist MRS-1754restored CIITA-dependent MHC IItransactivation. Forskolin, an adenylyl cyclase activator, achieved the same effect asNECA. A2b signaling repressed CIITA transcription by altering histonemodifications and recruitment of key factors on the type III and type IV promotersin a STAT1-dependent manner. MRS-1754blocked the antagonism of TGF-β in theinduction of CIITA expression by IFN-γ, alluding to a potential dialogue betweenTGF-β and adenosine signaling pathways. In conclusion, we have demarcated anadenosine-A2b receptor-adenylyl cyclase axis that influences CIITA-mediated MHC II transactivation in lung fibroblast cells and as such have provided invaluableinsights in the development of novel immune-modulatory strategies. Chapter2SIRT1deacetylates RFX5and antagonizes repression of collagentype I (COL1A2) transcription in smooth muscle cellsDecreased expression of collagen by vascular smooth muscle cells (SMCs) withinthe atherosclerotic plaque contributes to the thinning of the fibrous cap and poses agreat threat to plaque rupture. Elucidation of the mechanism underlying repressedcollagen type I (COL1A2) gene would potentially provide novel solutions that canprevent rupture-induced complications. We have previously shown that regulatoryfactor for X-box (RFX5) binds to the COL1A2transcription start site and repressesits transcription. Here we report that SIRT1, an NAD-dependent, class IIIdeacetylase, forms a complex with RFX5. Over-expression of SIRT1or NAMPT,which synthesizes NAD+to activate SIRT1, or treatment with the SIRT1agonistresveratrol decreases RFX5acetylation and disrupts repression of the COL1A2promoter activity by RFX5. On the contrary, knockdown of SIRT1or treatment withSIRT1inhibitors induces RFX5acetylation and enhances the repression of collagentranscription. SIRT1antagonizes RFX5activity by promoting its nuclear expulsionand proteasomal degradation hence dampening its binding to the COL1A2promoter.The pro-inflammatory cytokine IFN-γ represses COL1A2transcription bydown-regulating SIRT1expression in SMCs. Therefore, our data have identified asnovel pathway whereby SIRT1maintains collagen synthesis in SMCs by modulatingRFX5activity.