Cross talk between smooth muscle cells and monocytes/activated monocytes via CX3CL1/CX3CR1 axis augments expression of pro-atherogenic molecules

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• 作者：Elena Dragomir  ; Butoi^a ;   ; ^{elena.dragomir@icbp.ro} ; Ana Maria  ; Gan^a ;   ; ^{anca.gan@icbp.ro} ; Ileana  ; Manduteanu^a ;   ; ^{ileana.manduteanu@icbp.ro} ; Daniela  ; Stan^a ;   ; ^{daniela.stan@icbp.ro} ; Manuela  ; Calin^a ;   ; ^c ;   ; ^{manuela.calin@icbp.ro} ; Monica  ; Pirvulescu^a ;   ; ^{monica.pirvulescu@icbp.ro} ; Rory Ryan  ; Koenen^b ;   ; ^{rkoenen@ukaachen.de} ; Christian  ; Weber^b ;   ; ^{cweber@ukaachen.de} ; Maya  ; Simionescu^a ;   ; ^{maya.simionescu@icbp.ro}
• 关键词：Smooth muscle cell ; Monocyte ; Fractalkine ; CX3CR1 ; Inflammatory cytokine ; Metalloproteinase
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Cell Research
• 出版年：2011
• 出版时间：December 2011
• 年：2011
• 卷：1813
• 期：12
• 页码：2026-2035
• 全文大小：626 K

文摘

Objective

In atherosclerotic lesions, fractalkine (CX3CL1) and its receptor (CX3CR1) expressed by smooth muscle cells (SMC) and monocytes/macrophages, mediate the heterotypic anchorage and chemotaxis of these cells. We questioned whether, during the close interaction of monocytes with SMC, the CX3CL1/CX3CR1 pair modulates the expression of pro-atherogenic molecules in these cells.

Methods and results

SMC were co-cultured with monocytes or LPS-activated monocytes (18 h) and then the cells were separated and individually investigated for the gene and protein expression of TNF¦Á, IL-1¦Â, IL-6, CX3CR1 and metalloproteinases (MMP-2, MMP-9). We found that SMC¨Cmonocyte interaction induced, in each cell type, an increased mRNA and protein expression of TNF¦Á, IL-1¦Â, IL-6, CX3CR1, MMP-2 and MMP-9. Blocking the binding of fractalkine to CX3CR1 (by pre-incubation of monocytes with anti-CX3CR1 or by CX3CR1 siRNA transfection) before cell co-culture decreased the production of TNF¦Á, CX3CR1 and MMP-9. Monocyte¨CSMC interaction induced the phosphorylation of p38MAPK and activation of AP-1 transcription factor. Silencing the p65 (NF-kB subunit) inhibited the IL-1¦Â and IL-6 and silencing c-jun inhibited the TNF¦Á, CX3CR1 and MMP-9 induced by SMC¨Cmonocyte interaction.

Conclusions

The cross-talk between SMC and monocytes augments the inflammatory response in both cell types as revealed by the increased expression of TNF¦Á, IL-1¦Â, IL-6, CX3CR1 and MMPs. Up-regulation of TNF¦Á, CX3CR1 and MMP-9 is further increased upon interaction of SMC with activated monocytes and is dependent on fractalkine/CXRCR1 pair. These data imply that the fractalkine/CX3RCR1 axis may represent a therapeutic target to impede the inflammatory process associated with atherosclerosis.