The TNFα locus is altered in monocytes from patients with systemic lupus erythematosus

Abstract

In systemic lupus erythematosus, TNFα is elevated in the serum and correlates with disease activity and triglyceride levels. The stimuli that drive TNFα in this setting are incompletely understood. This study was designed to evaluate monocyte chromatin at the TNFα locus to identify semi-permanent changes that might play a role in altered expression of TNFα. SLE patients with relatively quiescent disease (mean Physician Global Assessment=0.6) and healthy controls were recruited for this study. TNFα expression was measured by intracellular cytokine staining of different monocyte subsets in patients (n=24) and controls (n=12). Histone acetylation at the TNFα locus was measured by chromatin immunoprecipitation using a normalized quantitative PCR in patients (n=46) and controls (n=24). There were no differences in the overall fractions of cells expressing CD14 in SLE patients compared to controls, however, the fraction of DR+/CD16+ cells expressing CD14 was slightly higher as was true in the monocyte subset defined by DR+/CD11b+. Within the monocyte population defined by physical characteristics and DR+/CD14+, TNFα expressing cells were more frequent in SLE patients compared to controls. Both the fraction of positive cells and the mean fluorescence intensity were higher in patients than controls. Consistent with this was the finding that monocytes from patients had increased TNFα transcripts and more highly acetylated histones at the TNFα locus compared to controls. Furthermore, patients with the highest levels of TNFα histone acetylation were more likely to have had consistently elevated erythrocyte sedimentation rates, and to have required cytotoxic use. Histone acetylation, associated with increased transcriptional competence of TNFα, may play a role in certain inflammatory aspects of the disease.

ITGAM coding variant (rs1143679) influences the risk of renal disease, discoid rash and immunological manifestations in patients with systemic lupus erythematosus with European ancestry

“…ITGAM (CD11b) expression was shown to increase DNA fragmentation, a prerequisite for apoptosis, and the level of fragmented DNA is increased in intravascular cells, which induces interferon α in SLE mice 9. CD11b also induces tumour necrosis factor α10 and modulates the innate immune mechanism11 in patients with SLE. This suggests that the association of this SNP in ITGAM with the molecular mechanism of immunological manifestations may be correlated.…”

Aberrant regulation of the integrin very late antigen-4 in systemic lupus erythematosus

“…The SLE patients in this study were recruited from a well-known cohort 40 in which a cumulative SLE database has been constructed for each patient. We specifically recruited subjects with low disease activity and who were not receiving high-level immune suppression or biologic therapy.…”

Transcriptional Control of the TNF Gene

“…Increased histone H3 and H4 acetylation at the TNF promoter region (and, in some cases, at the third intron of TNF) in primary human monocytes or human monocytic cell lines (e.g. THP-1) has been associated with induction of TNF transcription by LPS [186, 187] and high glucose concentrations [181], maturation of monocytes to macrophages [188], diabetes [181], and systemic lupus erythematosus [189]. Moreover, IFN-γ treatment of primary human monocytes led to increased, persistent H4 acetylation along with recruitment of ATF-2 and RNA Pol II, yielding a ‘poised’ pretranscription state and, subsequently, elevated LPS-induced levels of both TNF transcription and histone H3 and H4 acetylation at the TNF promoter [187].…”