Transglutaminase 2 null macrophages respond to lipopolysaccharide stimulation by elevated proinflammatory cytokine production due to an enhanced αvβ3 integrin-induced Src tyrosine kinase signaling

Sarang, Zsolt; Köröskényi, Krisztina; Pallai, Anna; Duró, Edina; Melino, Gerry; Griffin, Martin; Fésüs, László; Szondy, Zsuzsanna

doi:10.1016/j.imlet.2011.03.004

Cited by 22 publications

(15 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this stage c-SRC is still active and drives cytoskeletal dynamics and cell motility by stimulation of actin polymerization (Takai et al, 2001 ; Quack et al, 2009 ). Furthermore, c-SRC is increased in monocytes and macrophages and mediates secretion of pro-inflammatory cytokines (Sarang et al, 2011 ; Yokoi et al, 2011 ), which may contribute to HSC activation upon liver damage.…”

Section: Discussionmentioning

confidence: 99%

Interplay of Matrix Stiffness and c-SRC in Hepatic Fibrosis

et al. 2015

View full text Add to dashboard Cite

Introduction: In liver fibrosis activation of hepatic stellate cells (HSC) comprises phenotypical change into profibrotic and myofibroplastic cells with increased contraction and secretion of extracellular matrix (ECM) proteins. The small GTPase RhoA orchestrates cytoskeleton formation, migration, and mobility via non-receptor tyrosine-protein kinase c-SRC (cellular sarcoma) in different cells. Furthermore, RhoA and its downstream effector Rho-kinase also play a crucial role in hepatic stellate cells and hepatic fibrogenesis. Matrix stiffness promotes HSC activation via cytoskeleton modulation. This study investigated the interaction of c-SRC and RhoA under different matrix stiffness conditions.Methods: Liver fibrosis was induced in rats using bile duct ligation (BDL), thioacetamide (TAA) or carbon tetrachloride (CCl4) models. mRNA levels of albumin, PDGF-R, RHOA, COL1A1, and αSMA were analyzed via qRT-PCR. Western Blots using phospho-specific antibodies against p-c-SRC418 and p-c-SRC530 analyzed the levels of activating and inactivating c-SRC, respectively. LX2 cells and hepatocytes were cultured on acrylamide gels of 1 and 12 kPa or on plastic to mimic non-fibrotic, fibrotic, or cirrhotic environments then exposed to SRC-inhibitor PP2. Overexpression of RhoA was performed by transfection using RhoA-plasmids. Additionally, samples from cirrhotic patients and controls were collected at liver transplantations and tumor resections were analyzed for RhoA and c-SRC protein expression by Western Blot.Results: Transcription of albumin and RhoA was decreased, whereas transcription and activation of c-SRC was increased in hepatocytes cultured on 12 kPa compared to 1 kPa gels. LX2 cells cultured on 12 kPa gels showed upregulation of RHOA, COL1A1, and αSMA mRNA levels. Inhibition of c-SRC by PP2 in LX2 cells led to an increase in COL1A1 and αSMA most prominently in 12 kPa gels. In LX2 cells with RhoA overexpression, c-SRC inhibition by PP2 failed to improve fibrosis. RhoA expression was significantly elevated in human and experimental liver fibrosis, while c-SRC was inactivated.Conclusions: This study shows that c-SRC is inactive in activated myofibroblast-like HSC in liver cirrhosis. Inactivation of c-SRC is mediated by a crosstalk with RhoA upon hepatic stellate cell activation and fibrosis progression.

show abstract

Section: Discussionmentioning

confidence: 99%

Interplay of Matrix Stiffness and c-SRC in Hepatic Fibrosis

et al. 2015

View full text Add to dashboard Cite

show abstract

“…It has also been shown to control production of cytokine TNF-alpha stimulated by LPS in normal cells (Orlicek et al, 1999; Sarang et al, 2011; Okenwa et al, 2013). Thus, Src affects both innate and adaptive immune responses in normal cells.…”

Section: Src Activation Contributes To Both Inflammation and Cancer Imentioning

confidence: 99%

Src as the link between inflammation and cancer

et al. 2014

View full text Add to dashboard Cite

Although a causal link between chronic inflammation and cancer has been established, the exact molecular mechanism linking inflammation to cancer remains largely unknown. It was previously postulated that molecular switches responsible for cancer cell development, and for infiltration of inflammatory cells into cancer, were divided into a distinct set of intracellular proteins and signaling pathways. However, recent evidence suggests that both tumor cells and tumor-infiltrating immune cells utilize the same kinases, mostly that of Src family, to facilitate cancer development and progression. In the past few years several groups have found that Src activation both in cancer and inflammatory cells is mainly driven by pro-inflammatory cytokines within the tumor microenvironment. Here we evaluate the cross talks between Src kinase pathways in immune cells and cancer cells. We conclude that Src might serve as a critical mechanistic link between inflammation and cancer, mediating and propagating a cycle between immune and tissue cells that can ultimately lead to the development and progression of cancer.

show abstract

“…In this stage c-SRC is still active and drives cytoskeletal dynamics and cell motility by stimulation of actin polymerization (Takai et al, 2001;Quack et al, 2009). Furthermore, c-SRC is increased in monocytes and macrophages and mediates secretion of pro-inflammatory cytokines (Sarang et al, 2011;Yokoi et al, 2011), which may contribute to HSC activation upon liver damage.…”

Section: Discussionmentioning

confidence: 99%