Role of spleen tyrosine kinase in liver diseases

Table 1 Summary of pre-clinical and clinical studies using spleen tyrosine kinase inhibitors

Compound	Medical condition	Description/effect	Ref.
Fostamatinib (R788)	Ulcerative colitis	Suppression of TNFα, T cells and neutrophils	[106]
	Rheumatoid arthritis	Reduced inflammation and tissue damage, suppressed clinical arthritis, pannus formation and synovitis	[107,108]
	Chronic lymphocytic leukemia and Non-Hodgkin lymphoma	Disruption of BCR signaling inhibiting the proliferation and survival of malignant B cells	[109,110]
	Ischemia-reperfusion induced intestinal and lung damage	Impaired release of pro-inflammatory and coagulation mediators, reduced neutrophils, macrophages and platelet accumulations	[111]
	Glomerulonephritis	Reduced proteinuria, glomerular macrophage and CD8 cells, MCP-1 and IL-1β, and renal injury	[112]
Entospletinib (GS-9973)	Chronic lymphocytic leukemia	Decreased inflammation and disruption of chemokine/cytokine circuits (BCR signaling)	[113-115]
	Diffuse large B-cell lymphoma	Disruption of BCR signaling inhibiting the proliferation and survival of malignant B cells	[116]
	Cherubisme (craniofacial disorder)	Ameliorates inflammation and bone destruction in the mouse model of cherubism	[117]
Cerdulatinib (PRT062070)	Diffuse large B-cell lymphoma	Disruption of BCR signalling inhibiting the proliferation and survival of malignant B cells	[118,119]
TAK-659	Epstein-Barr virus-associated lymphoma	Inhibited tumour development and metastases	[120]
	Chronic lymphocytic leukemia	Decreased tumour survival, myeloid cell proliferation and metastasis	[121]
R406 (tamatinib)	Immunocomplexes mediated inflammation	Inhibits several critical modes of the inflammatory cascade	[122]
	Human platelets	Inhibition of activation of CLEC-2 (C-type lectin 2, platelet receptor), and platelet activation	[123]
	Chronic lymphocytic leukemia	Inhibition of constitutive and BCR-induced SYK activation, abrogation of CLL cell survival, migration, and paracrine signalling	[124]
	Leukemia	Reduced tyrosine phosphorylation and c-Myc expression, blockade of tumorigenic cells proliferation transformed by oncogenes	[125]
	Megakaryocytic leukemia	Induced apoptosis, reduced cell proliferation and blockade of STAT5 signalling	[126]
	Glomerulonephritis	Downregulated MCP-1 production from mesangial cells and macrophages	[112]
Piceatannol	Oral squamous cell carcinoma	Inhibited tumour cell proliferation, induced of apoptosis, attenuated VEGF and MMP9 expression, and decreased metastases	[127]

TNF-α: Tumour necrosis factor α; BCR: B-cell receptor; MCP-1: Monocyte chemoattractant protein 1; SYK: Spleen tyrosine kinase; VEGF: Vascular endothelial growth factor.

Table 2 Spleen tyrosine kinase inhibitors implicated in liver diseases

Inhibitor	Mechanism of action	Therapeutic effect	Ref.
R406	Blocking of Fc receptor signalling pathway, NF-κB signalling pathway and inflammasome activation	Reduced SYK expression and phosphorylation resulting in attenuated liver steatosis, inflammation and fibrosis in ASH and NASH murine models	[20,44]
GS-9973	Decreased expression of HSCs activation (CBP, MYB, MYC) and HSCs proliferation factors (MYC and CCND1)	Inhibition of HSCs proliferation and HSC activation resulting in amelioration of fibrosis and hepatocarcinogenesis	[28]
PRT062607 and piceatannol	Increased intra-tumoral p16, p53 and decreased expression of Bcl-xL and SMAD4. Decreased expression of genes regulating angiogenesis, apoptosis, cell cycle regulation and cellular senescence. Down-regulation of mTOR, IL-8 signalling and oxidative phosphorylation	Reduced HSCs differentiation and infiltration of inflammatory cells including T cells, B cells and myeloid cells, reduced oncogenic progression. Marked attenuation of toxin-induced liver fibrosis, associated hepatocellular injury, intra-hepatic inflammation and hepatocarcinogenesis	[128]

SYK: Spleen tyrosine kinase; NASH: Non-alcoholic steatohepatitis; ASH: Alcoholic steatohepatitis; HSCs: Hepatic stellate cells; IL-8: Interleukin-8.