DC isoketal-modified proteins activate T cells and promote hypertension
Autor: | Raymond L. Mernaugh, Kenneth E. Bernstein, Mohamed A. Saleh, Daniel W. Trott, Ana Paula Faria, Yu Shyr, Sheau-Chiann Chen, Wei Chen, Annet Kirabo, Christi L Galindo, Jing Wu, Liang Xiao, Xiao Z. Shen, Kalyani Amarnath, Meena S. Madhur, Cheryl L. Laffer, Venkataraman Amarnath, Vanessa Fontana, Fernando Elijovich, Tomasz J. Guzik, L. Jackson Roberts, Hana A. Itani, Heitor Moreno, Roxana Loperena, Alfiya T Bikineyeva, David G. Harrison, Sean S. Davies, Sergey Dikalov, Antony Vinh |
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Jazyk: | angličtina |
Rok vydání: | 2014 |
Předmět: |
Male
T cell T-Lymphocytes Interleukin-1beta Antigen-Presenting Cells Mice Transgenic Inflammation Biology Kidney Lymphocyte Activation Interleukin-23 Cohort Studies Mice Superoxides medicine Animals Humans Antigen-presenting cell Aged Cell Proliferation CD86 Aldehydes Interleukin-6 Angiotensin II Interleukin-17 General Medicine Dendritic cell Dendritic Cells Middle Aged Oxygen Oxidative Stress medicine.anatomical_structure Gene Expression Regulation Immunology Hypertension B7-1 Antigen Commentary Cancer research Female B7-2 Antigen medicine.symptom CD80 CD8 Research Article |
Popis: | Oxidative damage and inflammation are both implicated in the genesis of hypertension; however, the mechanisms by which these stimuli promote hypertension are not fully understood. Here, we have described a pathway in which hypertensive stimuli promote dendritic cell (DC) activation of T cells, ultimately leading to hypertension. Using multiple murine models of hypertension, we determined that proteins oxidatively modified by highly reactive γ-ketoaldehydes (isoketals) are formed in hypertension and accumulate in DCs. Isoketal accumulation was associated with DC production of IL-6, IL-1β, and IL-23 and an increase in costimulatory proteins CD80 and CD86. These activated DCs promoted T cell, particularly CD8+ T cell, proliferation; production of IFN-γ and IL-17A; and hypertension. Moreover, isoketal scavengers prevented these hypertension-associated events. Plasma F2-isoprostanes, which are formed in concert with isoketals, were found to be elevated in humans with treated hypertension and were markedly elevated in patients with resistant hypertension. Isoketal-modified proteins were also markedly elevated in circulating monocytes and DCs from humans with hypertension. Our data reveal that hypertension activates DCs, in large part by promoting the formation of isoketals, and suggest that reducing isoketals has potential as a treatment strategy for this disease. |
Databáze: | OpenAIRE |
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