The effect of ARVs on the <i>MEKKK1</i> gene promoter, inflammatory cytokine expression and signalling in acute treated Jurkat T cells
Creators: name: Moses, Avril Kirsten
name: Ghazi, Terisha
name: Nagiah, Savania
name: Chuturgoon, Anil
Publisher: name: Taylor & Francis
Year: 2023
Subjects: subject: Biochemistry
subject: Microbiology
subject: FOS: Biological sciences
subject: Cell Biology
subject: Genetics
subject: Molecular Biology
subject: Physiology
subject: Pharmacology
subject: Biotechnology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: Science Policy
subject: Immunology
subject: FOS: Clinical medicine
subject: 69999 Biological Sciences not elsewhere classified
subject: Developmental Biology
subject: Cancer
subject: Hematology
subject: 110309 Infectious Diseases
subject: FOS: Health sciences
subject: Plant Biology

description: ARVs alter the methylation status of the <i>MEKKK1</i> gene promoter in acute treated Jurkat T cells with inflammatory outcomesInflammation is reduced in patients under going antiretroviral therapy; however the mechanism is not well understood. We investigated DNA methylation of the mitogen-activated protein kinase kinase kinase kinase 1 (<i>MEKKK1</i>) gene promoter in Jurkat T cells to determine whether the antiretroviral drugs, lamivudine, tenofovir disoproxil fumarate, dolutegravir, TLD (a combination of TDF, 3TC and DTG) and efavirenz modify the methylation status of the <i>MEKKK1</i> gene – a known stimulus of inflammation.Acute antiretroviral treatments (24 h) were not cytotoxic to Jurkat T cells. <i>MEKKK1</i> promoter hypomethylation occurred in cells treated with 5-aza-2’-deoxycytidine (Aza), TDF and 3TC, and <i>MEKKK1</i> promoter hypermethylation occurred in cells treated with DTG; however, promoter DNA methylation of the <i>MEKKK1</i> gene did not influence <i>MEKKK1</i> gene expression; therefore, these drugs did not epigenetically regulate <i>MEKKK1</i> and downstream signalling by promoter DNA methylation. Acute TLD and EFV treatments induced inflammation in Jurkat T cells by increasing MEKKK1, MAPK/ERK and NFκB expression, and activating <i>tumour necrosis factor-α</i> (<i>TNF-α</i>) expression. ARVs decreased <i>IL-10</i> gene expression, showing no anti-inflammatory activity.The data shows that the inflammation caused by ARVs is not related to the methylation status of <i>MEKKK1</i> gene promoter and suggests an alternative stimulus <i>via</i> post-transcriptional/post-translational modifications may activate the canonical MEKKK1/NFκB pathway that leads to inflammation. Finally, an increase in NFκB activity and pro-inflammatory cytokine activation seemed to occur <i>via</i> the MAPK/ERK pathway following ARV treatments in Jurkat T cells. Inflammation is reduced in patients under going antiretroviral therapy; however the mechanism is not well understood. We investigated DNA methylation of the mitogen-activated protein kinase kinase kinase kinase 1 (<i>MEKKK1</i>) gene promoter in Jurkat T cells to determine whether the antiretroviral drugs, lamivudine, tenofovir disoproxil fumarate, dolutegravir, TLD (a combination of TDF, 3TC and DTG) and efavirenz modify the methylation status of the <i>MEKKK1</i> gene – a known stimulus of inflammation. Acute antiretroviral treatments (24 h) were not cytotoxic to Jurkat T cells. <i>MEKKK1</i> promoter hypomethylation occurred in cells treated with 5-aza-2’-deoxycytidine (Aza), TDF and 3TC, and <i>MEKKK1</i> promoter hypermethylation occurred in cells treated with DTG; however, promoter DNA methylation of the <i>MEKKK1</i> gene did not influence <i>MEKKK1</i> gene expression; therefore, these drugs did not epigenetically regulate <i>MEKKK1</i> and downstream signalling by promoter DNA methylation. Acute TLD and EFV treatments induced inflammation in Jurkat T cells by increasing MEKKK1, MAPK/ERK and NFκB expression, and activating <i>tumour necrosis factor-α</i> (<i>TNF-α</i>) expression. ARVs decreased <i>IL-10</i> gene expression, showing no anti-inflammatory activity. The data shows that the inflammation caused by ARVs is not related to the methylation status of <i>MEKKK1</i> gene promoter and suggests an alternative stimulus <i>via</i> post-transcriptional/post-translational modifications may activate the canonical MEKKK1/NFκB pathway that leads to inflammation. Finally, an increase in NFκB activity and pro-inflammatory cytokine activation seemed to occur <i>via</i> the MAPK/ERK pathway following ARV treatments in Jurkat T cells.