Host Cell Cytokines Induced by Chlamydia pneumoniae Decrease the Expression of Interstitial Collagens and Fibronectin in Fibroblasts

Abstract

Chlamydia pneumoniae infection has been associated with chronic obstructive airway disease (COPD), asthma, and atherosclerosis. Inflammation and airway remodeling in asthma and COPD result in subepithelial fibrosis that is characterized by the deposition of interstitial collagens and fibronectin. The progression of atherosclerosis is also accompanied by an increased production of interstitial collagens in the intima. As shown by reverse transcription-PCR and immunoblotting, infection of human fibroblasts and smooth muscle cells by C. pneumoniae TW-183 downregulated the expression of type I and III collagen and fibronectin, whereas the level of type IV collagen remained unchanged. Conditioned medium from infected fibroblasts as well as epithelial WISH cells also reduced the expression of interstitial collagens and fibronectin in uninfected cells. In experiments using blocking antibodies, beta interferon was found to contribute to the inhibitory effects of conditioned medium collected from infected fibroblasts. In contrast, downregulation of matrix protein expression by conditioned medium from epithelial cells was caused by interleukin-1␣, which was not secreted from fibroblasts following chlamydial infection. C. pneumoniae-mediated inhibition of collagen and fibronectin expression was diminished following transfection of fibroblasts with specific small interfering RNA targeting the transcription factor CCAAT/enhancer-binding protein ␤. The downregulation of interstitial collagens and fibronectin by the Chlamydia-induced host cell cytokine response may modulate tissue remodeling processes in airway diseases. In atherosclerosis the inhibition of collagen synthesis by C. pneumoniae infection may promote plaque vulnerability, thereby increasing the risk of plaque rupture.

The sst1 Resistance Locus Regulates Evasion of Type I Interferon Signaling by Chlamydia pneumoniae as a Disease Tolerance Mechanism

“…While respiratory infection is often subclinical or mildly symptomatic, chronic infection with C. pneumoniae has been suggested as a trigger or promoter of a number of inflammatory conditions, including asthma (reviewed in [12], [13]), chronic obstructive pulmonary disease (COPD) [14], and atherosclerosis (reviewed in [15]). The mechanism by which C. pneumoniae can disseminate from the lung remains unproven, but one leading model suggests that replication within lung macrophages provides a unique niche for transport to distant sites, such as chronic vascular lesions (reviewed in [15]), and case reports have identified C. pneumoniae within atherosclerotic lesions [16], [17].…”

CCAAT/Enhancer-Binding Proteins in Fibrosis: Complex Roles Beyond Conventional Understanding

“…Recent studies have shown that C/EBPβ and C/EBPγ participated in skin fibrosis through different mechanisms [249,250] (Figure 8). In dermal fibroblasts, Col1α1 and Col1α2 are target genes of C/EBPβ and increased C/EBPβ expression induced by inflammatory factors, such as interferon beta (IFN-β) and IFN-γ, inhibits not only Col1α1 and Col1α2 expression but also the levels of Col3α1 and fibronectin, which suppresses ECM deposition [210,211,361]. In addition, a recent report showed that C/EBPγ can promote skin wound healing, indicating that C/EBPγ may play an important role in fibroblast activation.…”

“…However, C/EBP β protein level is also induced by IL-1 β in lung fibroblasts, with a greater increase in C/EBP β -LIP isoform expression leading to a reduced LAP/LIP ratio and reduced α -SMA promoter activity and expression [ 209 ]. This may explain why treatment with inflammatory factors increases C/EBP β expression and decreases fibroblast activation [ 210 , 211 ].…”

Comparative analysis of the growth and biological activity of a respiratory and atheroma isolate of Chlamydia pneumoniae reveals strain-dependent differences in inflammatory activity and innate immune evasion

“…While most respiratory-acquired infections are asymptomatic or mild, it can result in pneumonia, usually involving a single lobe, and complications including life-threatening pneumonia and acute respiratory distress syndrome have been reported [ 4 – 6 ]. In addition, a number of human and animal studies suggest that C. pneumoniae infection can trigger or promote chronic inflammatory conditions, including reactive airway disease and adult-onset asthma (reviewed in [ 7 , 8 ]), chronic obstructive pulmonary disease [ 9 ], and atherosclerosis (reviewed in [ 10 – 12 ]).…”