HLA‐B35 upregulates the production of endothelin‐1 in HLA‐transfected cells: a possible pathogenetic role in pulmonary hypertension

Abstract

HLA-B35 is associated with an increased risk for developing isolated pulmonary hypertension (iPHT) in systemic sclerosis, but the mechanisms underlying this association have not been fully elucidated yet. Endothelin-1 (ET-1) is the main pathogenetic molecule implied in the development of iPHT; therefore, we sought to determine if ECV304 cells transfected with the HLA-B35 allele produce increased amounts of ET-1 after incubation with physiological concentrations of interleukin-1 beta (IL-1beta). ECV304 cells transfected with HLA-B*3501 and HLA-B*0801 polymorphic alpha chain or with pIRESneo2 were incubated with 100 U/ml of IL-1beta for 6, 12, 24, 36 and 48 h. ET-1 levels were determined using EIA kit (CAYMAN Chemical, Ann Arbor, MI) in supernatants from different cell cultures; the relative expression of the preproendothelin-1 (PPET-1) gene was also determined by reverse transcription-polymerase chain reaction. Cells expressing the HLA-B35 allele showed significantly increased levels of ET-1 at all the selected times compared with controls or HLA-B8-transfected cells. The relative expression of the PPET-1 gene was also increased in a proportionally direct manner. The HLA-B35 allele influences the production of ET-1 in HLA-B35-transfected ECV304 cells by promoting the expression of its precursor, PPET-1. Our results provide an explanation for the epidemiological association existing between iPHT and HLA-B35.

HLA-B35 Upregulates Endothelin-1 and Downregulates Endothelial Nitric Oxide Synthase via Endoplasmic Reticulum Stress Response in Endothelial Cells

“…Apoptosis is known to be an important factor in causing lymphocyte depletion in acquired AIDS patients (28) and this process is further enhanced by the class I overexpression that is induced in tissues during viral infections. Our previous studies suggested that the upregulation of endothelin-1 (ET-1) in activated HLA-B35–positive endothelial cells (ECs) (29) may be the basis of the association between HLA-B35 allele and the isolated pulmonary hypertension (iPHT) in Italian scleroderma (SSc) patients (30, 31). However, the mechanisms underlying this association have not been fully elucidated.…”

Association of Chlamydia pneumoniae Infection with HLA-B*35 in Patients with Coronary Artery Disease

“…C. pneumoniae-infected monocyte cells are shown to up-regulate many genes including the vasoconstrictor endothelin 1 (41). HLA-B*35 influences the upregulation of endothelin 1, providing an explanation for the epidemiological association existing between isolated pulmonary hypertension and HLA-B*35 (38).…”

“…The HLA-B*35 allele has been shown to confer a significant proapoptotic influence to different kind of cells. It may promote pathological cell activation and proliferation and gene transcription through the control of the intracellular cation concentration (38). C. pneumoniae-infected monocyte cells are shown to up-regulate many genes including the vasoconstrictor endothelin 1 (41).…”

HLA Markers for Poor Prognosis in Systemic Sclerosis Brazilian Patients

“…The association with HLA-B*35 had already been described, and this allele appears to be involved in the upregulation of ET-1 and the pathogenesis of PAH [27, 28]. Gladman et al found a significant association between PAH and the HLA-A*30, B*13, B*65, and DRB1*03 alleles [4].…”

“…Some class I alleles were also related, such as A*30, B*13, B*65 [4], and B*35, which appear to play a role in the production of endothelin-1 (ET-1) in SSc [27, 28]. HLA-DRB1*01, DRB1*03, and DQB1*0501 were also related to PAH and ACA [29, 30].…”