The role of tyrosine kinases in systemic lupus erythematosus and their potential as therapeutic targets

Shao, Wen‐Hai; Cohen, Philip L.

doi:10.1586/1744666x.2014.893827

Cited by 25 publications

(19 citation statements)

References 81 publications

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“…SLE is a chronic systemic autoimmune disease affecting the connective tissue marked by alternate periods of remission and exacerbation [20,21]. SLE may affect multiple organs leading to serious complications, most prominently the kidney and the central nervous system [22].…”

Section: Slementioning

confidence: 99%

Possible evidence of systemic lupus erythematosus and periodontal disease association mediated by Toll-like receptors 2 and 4

Marques

Maor

Andrade

et al. 2015

Clinical and Experimental Immunology

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Summary Toll‐like receptors (TLRs) participate in the innate immune response and trigger the immune responses of the body. Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown aetiology, characterized by an excessive autoimmune response in the body affecting the connective tissues. The disease is possibly triggered by both environmental aetiological factors and pathological organic processes such as exposure to sunlight, chronic infectious processes and genetic factors. Conversely, periodontal disease is an infectious disease caused by microorganisms in the oral cavity, resulting in a chronic inflammatory process which continuously stimulates the immune response, thus causing damage to the periodontal tissues. The expression of both TLR‐2 and TLR‐4 receptors are increased in both SLE and periodontal disease. Periodontitis might trigger excessive activation of immune response occurring in SLE by maintaining a high expression of TLRs, leading in turn to the acceleration of the onset and progression of autoimmune reactions. In addition, periodontal treatment is able to reduce the expression of these receptors and therefore the symptoms of SLE. Here we discuss the possible interaction between SLE and periodontitis, and suggest further studies evaluating common features in both factors that could explored, due to morbidity and mortality of SLE and the high incidence of periodontal infections around the world.

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Section: Slementioning

confidence: 99%

Possible evidence of systemic lupus erythematosus and periodontal disease association mediated by Toll-like receptors 2 and 4

Marques

Maor

Andrade

et al. 2015

Clinical and Experimental Immunology

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“…In fibroblasts, TGF-β-induced CTGF is 2 of 17 dependent on Smad3 and transducer and activator of transcription 3 (STAT3) are involved in activated CTGF [8]. The SRC kinase family comprises non-receptor tyrosine kinases, including Src, Fyn, Yes, and Lyn [9,10]. Src was originally identified as an oncogene and it is expressed in human tumors; however, it is also ubiquitously expressed in all cell types.…”

Section: Introductionmentioning

confidence: 99%

“…Src was originally identified as an oncogene and it is expressed in human tumors; however, it is also ubiquitously expressed in all cell types. Src phosphorylates the signaling proteins STAT3, AKT, and epidermal growth factor receptor (EGFR), thereby regulating various biological activities, including cell survival, proliferation, and migration [10][11][12]. The activation of Src causes pulmonary and renal fibrosis [13,14].…”

Section: Introductionmentioning

confidence: 99%

Src Inhibition Attenuates Liver Fibrosis by Preventing Hepatic Stellate Cell Activation and Decreasing Connective Tissue Growth Factor

Seo

Lee

et al. 2020

Cells

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The SRC kinase family comprises non-receptor tyrosine kinases that are ubiquitously expressed in all cell types. Although Src is reportedly activated in pulmonary and renal fibrosis, little is known regarding its role in liver fibrosis. This study investigated whether the inhibition of Src protects against liver fibrosis. The expression of Src was upregulated in thioacetamide (TAA)-induced fibrotic mouse liver and cirrhosis of patients, and phospho-Src was upregulated during activation of hepatic stellate cells (HSC). In addition, Src inhibition reduced the expression of α-smooth muscle actin (αSMA) in primary HSCs and suppressed transforming growth factor β (TGF-β)-induced expression of connective tissue growth factor (CTGF) in hepatocytes. Src inhibitor Saracatinib also attenuated TAA-induced expression of type I collagen, αSMA, and CTGF in mouse liver tissues. The antifibrotic effect of Src inhibitors was associated with the downregulation of Smad3, but not of signal transducer and activator of transcription 3 (STAT3). In addition, Src inhibition increased autophagy flux and protected against liver fibrosis. These results suggest that Src plays an important role in liver fibrosis and that Src inhibitors could be treat liver fibrosis.

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“…Ibrutinib also ameliorated humoral and cellular autoimmunity by partial crippling of cell signaling in both B cells and antigen presenting cells in lupus–prone B6.Sle1 and B6.Sle1.Sle3 mice [ 25 ]. Thus, targeting the BTK signaling pathway may provide an effective therapeutic strategy [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

HM71224, a selective Bruton’s tyrosine kinase inhibitor, attenuates the development of murine lupus

et al. 2017

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BackgroundSystemic lupus erythematosus (SLE) is associated with B cell hyperactivity, and lupus nephritis (LN), in particular, is promoted by the production of autoantibodies and immune complex deposition. Bruton’s tyrosine kinase (BTK) plays critical roles in B cell receptor-related and Fc receptor-related signaling. We aimed to investigate the impact of therapeutic intervention with HM71224 (LY3337641), a selective BTK inhibitor, on the development of murine SLE-like disease features.MethodsWe examined the therapeutic effects of HM71224 on SLE-like disease features in MRL/lpr and NZB/W F1 mice. The disease-related skin lesion was macroscopically observed in MRL/lpr mice, and the impact on splenomegaly and lymphadenopathy was determined by the weight of the spleen and cervical lymph node. The renal function was evaluated by measuring blood urea nitrogen, serum creatinine, and urine protein, and the renal damage was assessed by histopathological grading. Survival rate was observed during the administration period. The impact of B cell inhibition was investigated in splenocytes from both mice using flow cytometry. Autoantibody was measured in serum by ELISA.ResultsHM71224 effectively suppressed splenic B220+GL7+, B220+CD138+, and B220+CD69+ B cell counts, and anti-dsDNA IgG and reduced splenomegaly and lymph node enlargement. The compound also prevented skin lesions caused by lupus development, ameliorated renal inflammation and damage with increased blood urea nitrogen and creatinine, and decreased proteinuria. Furthermore, HM71224 also decreased mortality from lupus development in both mouse models.ConclusionOur results indicate that inhibition of BTK by HM71224 effectively reduced B cell hyperactivity and significantly attenuated the development of SLE and LN in rodent SLE models.

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The role of tyrosine kinases in systemic lupus erythematosus and their potential as therapeutic targets

Cited by 25 publications

References 81 publications

Possible evidence of systemic lupus erythematosus and periodontal disease association mediated by Toll-like receptors 2 and 4

Possible evidence of systemic lupus erythematosus and periodontal disease association mediated by Toll-like receptors 2 and 4

Src Inhibition Attenuates Liver Fibrosis by Preventing Hepatic Stellate Cell Activation and Decreasing Connective Tissue Growth Factor

HM71224, a selective Bruton’s tyrosine kinase inhibitor, attenuates the development of murine lupus

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