Lymphocyte α-kinase is a gout-susceptible gene involved in monosodium urate monohydrate-induced inflammatory responses

Abstract

The molecular functions and pathophysiologic role of the lymphocyte α-kinase gene (ALPK1) in gout are unknown. We aimed to examine ALPK1 expression in patients with gout and investigate its role in monosodium urate monohydrate (MSU)-induced inflammatory responses. Microarray data mining was performed with six datasets containing three clinical gout and three volunteer samples. Real-time quantitative polymerase chain reaction (qPCR) assay was used to profile ALPK1 mRNA expression in 62 independent samples. RNA interference for ALPK1 suppression in THP1 cells (human monocytic cell line) was used to scrutinize the functional role of ALPK1 in MSU-mediated inflammatory responses, and ALPK1 expression in MSU-treated THP1 cells was determined by qPCR and Western blot analysis. Cytokine mRNA expression in HEK293 cells after incubation with different concentrations of MSU crystals in the presence or absence of ALPK1 was also detected by qPCR, and ERK1/2, p38, and JNK expressions were investigated by Western blot analysis. ALPK1 mRNA was overexpressed in the clinical gout samples. MSU treatment promoted ALPK1 expression at the mRNA and protein levels. Furthermore, ALPK1 knockdown in THP1 cells resulted in a markedly decreased IL-1β, TNF-α, and IL-8 mRNA expression; plasmid ALPK1 transfection and MSU stimulation synergistically increased the mRNA expression of these cytokines in a concentration-dependent manner. The synergistic effect also led to ERK1/2 activation. ALPK1 is a gout-susceptible gene involved in MSU-induced inflammatory responses. It may contribute to the development of gout by enhancing the inflammatory responses via the mitogen-activated protein kinase pathway.

Association of genetic variants with coronary artery disease and ischemic stroke in a longitudinal population-based genetic epidemiological study

“…rs2074381 of ALPK1 was significantly associated with CAD and ischemic stroke, with the GG genotype being protective against these conditions. These previous observations (27,41,(43)(44)(45)(46)(47)(48)(49)(50)(51)(52) and our present results suggest that ALPK1 may contribute to the development of CAD and ischemic stroke through the acceleration of vascular inflammation, although the molecular mechanisms underlying the role of rs2074381 of ALPK1 in the pathogenesis of CAD and ischemic stroke remain unknown.…”

“…ALPK1 functions in apical transport by phosphorylating myosin 1a in epithelial cells and is indicated in the regulation of intracellular trafficking processes by phosphorylation (40). ALPK1 may act synergistically with monosodium urate monohydrate crystals to promote the production of proinflammatory cytokines through the activation of nuclear factor-κB and mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2 and p38) signaling in cultured human embryonic kidney 293 (HEK293) cells, suggesting that ALPK1 may contribute to the inflammatory process associated with the development of gout (41). Our previous GWAS for chronic kidney disease showed that the overexpression of ALPK1 resulted in upregulation of the expression of cystatin C in cultured HEK293T cells (27).…”

Association of genetic variants of the α-kinase 1 gene with myocardial infarction in community-dwelling individuals

“…Those observations suggested that the correlation of ALPK1 to MI may be mediated by the effects of cystatin C on the development of vascular inflammation. Therefore, those observations (17)(18)(19)(21)(22)(23)(24) suggested that ALPK1 may contribute to the development of MI through the acceleration of vascular inflammation.…”

“…ALPK1 is expressed in various human tissues, including the heart and kidney (15) and was shown to be crucial in protein sorting and polarization in epithelial cells (16). ALPK1 may act synergistically with monosodium urate monohydrate crystals to promote the production of proinflammatory cytokines through the activation of nuclear factor-κB and mitogen-activated protein kinase (ERK1̸2 and p38) signaling in cultured HEK293 cells (17), indicating that ALPK1 may contribute to the inflammatory process associated with the development of gout. Since the onset of MI is likely precipitated by activated inflammation at atherosclerotic plaques in the coronary arterial wall (18,19), the association of ALPK1 to MI may be attributable to its effect on vascular inflammation.…”

Association of genetic variants of the α-kinase 1 gene with type 2 diabetes mellitus in a longitudinal population-based genetic epidemiological study

“…ALPK1 may act synergistically with monosodium urate monohydrate crystals to promote the production of proinflammatory cytokines through the activation of nuclear factor-κB and mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2 and p38) signaling in cultured HEK293 cells, suggesting that ALPK1 may contribute to the inflammatory process associated with the development of gout (39).…”