Transactivation of Src, PDGF receptor, and Akt is involved in IL‐1β‐induced ICAM‐1 expression in A549 cells

Abstract

In previous study, interleukin-1beta (IL-1beta) has been shown to induce ICAM-1 expression through MAPKs and NF-kappaB in A549 cells. In addition to these pathways, transactivation of non-receptor tyrosine kinase (Src), PDGF receptors (PDGFRs), and phosphatidylinositol 3-kinase (PI3K)/Akt has been implicated in the expression of inflammatory genes. Here, we further investigated whether these different mechanisms participating in IL-1beta-induced ICAM-1 expression in A549 cells. We initially observed that IL-1beta-induced ICAM-1 promoter activity was attenuated by the inhibitors of Src (PP1), PDGFR (AG1296), PI3-K (LY294002 and wortmannin), and Akt (SH-5), revealed by reporter gene assay, Western blotting, and RT-PCR analyses. The involvement of Src and PI3-K/Akt in IL-1beta-induced ICAM-1 expression was significantly attenuated by transfection of A549 cells with dominant negative plasmids of Src, p85 and Akt, respectively. Src, PDGFR, and PI3K/Akt mediated the effects of IL-1beta because pretreatment with PP1, AG1296, and wortmannin also abrogated IL-1beta-stimulated Src, PDGFR, and Akt phosphorylation, respectively. Moreover, pretreatment with p300 inhibitor (curcumin) also blocked ICAM-1 expression. We further confirmed that p300 was associated with ICAM-1 promoter which was dynamically linked to histone H4 acetylation stimulated by IL-1beta, determined by chromatin immunoprecipitation assay. Association of p300 and histone-H4 to ICAM-1 promoter was inhibited by LY294002. Up-regulation of ICAM-1 enhanced the adhesion of neutrophils onto A549 cell monolayer exposed to IL-1beta, which was inhibited by PP1, AG1296, LY294002, wortmannin, and helenalin. These results suggested that Akt phosphorylation mediated through transactivation of Src/PDGFR promotes the transcriptional p300 activity and eventually leads to ICAM-1 expression induced by IL-1beta.

Overexpression of HO-1 Protects against TNF-α-Mediated Airway Inflammation by Down-Regulation of TNFR1-Dependent Oxidative Stress

“…22 The Src family kinases have been shown to regulate ICAM-1 and VCAM-1 expression, NADPH oxidase activation, and ROS generation. [5][6][7]23 In our study, we also established that TNF-␣ induced adhesion molecules expression and ROS generation through TNFR1 and c-Src by pretreatment with an anti-TNFR1 neutralizing Ab or PP1. In addition, our data also showed that TNF-␣ induced adhesion molecules expression and NADPH oxidase activation via the formation of a TNFR1/c-Src/p47 phox complex in HTSMCs.…”

“…Several studies have indicated that the expression of VCAM-1 and ICAM-1 are mediated by the activation of c-Src, phosphatidylinositol 3-kinase /Akt, mitogen-activated protein kinases, or nuclear factor (NF)-B. 2,[5][6][7][8] In addition, ROS also have been shown to mediate NF -B activation and the expression of VCAM-1 and ICAM-1. 8 TNF-␣ may stimulate ROS production by several sources, such as mitochondria, but recent studies have strongly suggested that a major source of ROS is a phagocyte-type NADPH oxidase.…”

“…[5][6][7]23 Therefore, we investigated whether TNFR1 and c-Src involved in adhesion molecules expression, p47 phox translocation, and ROS production. Pretreatment with an anti-TNFR1 neutralizing Ab or a c-Src kinase inhibitor (PP1) attenuated TNF-␣-induced ICAM-1 and VCAM-1 protein levels ( Figure 4A).…”

Lack of evidence of stimulatory autoantibodies to platelet‐derived growth factor receptor in patients with systemic sclerosis

“…This is likely due to contamination of the antibodies with PDGF, which is released in serum in massive amounts by activated platelets, and with other molecules that are able to indirectly activate PDGFRs. This process, known as receptor transactivation, can be triggered by angiotensin II, inflammatory cytokines, drugs, and many other factors (25)(26)(27)(28). Such contaminants are difficult to trace because they are highly variable in terms of chemical structure and are active at low concentrations.…”

Targeted Delivery of Surface Modified Nanoparticles: Modulation of Inflammation for Acute Lung Injury

“…320 Due to a high chemokine gradient across the alveolar barrier, leukocytes infiltrate from blood circulation into alveoli, and exacerbate edema and lung inflammation. 321,322 Of the various transcriptional factors, NF-B plays a central role in regulating the inflammatory genes encoding CAMs, chemokines and cytokines. 75,323 NF-B is a heterodimeric protein present in the cytoplasm in an inactive form stabilized by binding to the inhibitory protein, I B .…”