Transcription factor complex AP-1 mediates inflammation initiated byChlamydia pneumoniaeinfection

Abstract

Summary Chlamydia pneumoniae is responsible for a high prevalence of respiratory infections worldwide and has been implicated in atherosclerosis. Inflammation is regulated by transcription factor (TF) networks. Yet, the core TF network triggered by chlamydiae remains largely unknown. Primary human coronary artery endothelial cells were mock-infected or infected with C. pneumoniae to generate human transcriptome data throughout the chlamydial developmental cycle. Using systems network analysis, the predominant TF network involved receptor, binding and adhesion, and immune response complexes. Cells transfected with interfering RNA against activator protein-1 (AP-1) members FOS, FOSB, JUN and JUNB had significantly decreased expression and protein levels of inflammatory mediators interleukin (IL)6, IL8, CD38 and tumor necrosis factor compared with controls. These mediators have been shown to be associated with C. pneumoniae disease. Expression of AP-1 components was regulated by MAPK3K8, a MAPK pathway component. Additionally, knockdown of JUN and FOS showed significantly decreased expression of Toll-like receptor (TLR)3 during infection, implicating JUN and FOS in TLR3 regulation. TLR3 stimulation led to elevated IL8. These findings suggest that C. pneumoniae initiates signaling via TLR3 and MAPK that activate AP-1, a known immune activator in other bacteria not previously shown for chlamydiae, triggering inflammation linked to C. pneumoniae disease.

Chromatin Profiling Reveals Regulatory Network Shifts and a Protective Role for Hepatocyte Nuclear Factor 4α during Colitis

“…1E, right). This is consistent with AP-1 and ETS roles in mediating the inflammatory response, as both families have been implicated in responding to tumor necrosis factor alpha signaling and have been reported to induce cytokine expression in endothelial and epidermal tissues (28)(29)(30)(31)(32). At genomic regions that lose enhancer chromatin structure upon inflammation, colonic developmental transcription factor motifs predominated (KLF, HNF4, and HNF1), suggesting that these regions lose their transcription factor occupancy during colitis (33)(34)(35)(36)(37).…”

Chlamydia trachomatis-Induced Alterations in the Host Cell Proteome Are Required for Intracellular Growth

“…The AP-1 complex is targeted by several bacterial pathogens to alter cellular survival or prevent inflammation and cytokine production, with some pathogens preventing activation and some inducing activation of upstream host signaling cascades (Alto and Orth, 2012). Interestingly, a recent report using C. pneumoniae suggested that AP-1 activation is responsible for inflammation seen in vivo (Wang et al, 2012). While the effect of AP-1 on inflammation during infection in vivo remains to be confirmed for C. trachomatis , these data together suggest that finely tuned AP-1 signaling is required for robust intracellular growth.…”

Small Molecule Inhibitors Targeting Activator Protein 1 (AP-1)

“…2,15,16 AP-1 protein is primarily regulated at the level of both Jun and Fos gene transcription involving mitogen-activated protein kinases (MAPKs) pathways and by post-translational modification via phosphorylation and dephosphorylation. 15 …”