362 research outputs found
HYPOXIA REGULATED RESPONSES IN THE PATHOGENESIS OF RHEUMATOID ARTHRITIS
Increased angiogenesis in the synovium is a hallmark of rheumatoid arthritis (RA),
and is thought to be driven by the presence of both local regions of reduced oxygen tension
(hypoxia) and inflammatory cytokines in the synovium. RA fibroblast-like synoviocytes
(FLS) are the main cell type at the proliferating and invading edge of the pannus, and are
therefore likely to be exposed to the greatest degree of hypoxia. In culture, RA FLS can
secrete a plethora of angiogenic factors in response to hypoxia and inflammatory cytokines,
and these cells are thus potential regulators of synovial angiogenesis. Transcriptional control
of many hypoxia-inducible genes, including several involved in angiogenesis, occurs via
hypoxia-inducible factor (HIF)-1α and/or HIF-2α, powerful transcription factors known to be
induced by hypoxia and cytokines.
The regulation of HIFs by hypoxia and inflammatory cytokines (tumour necrosis
factor α, interleukin-1β and transforming growth factor β) was studied in RA FLS. The main
findings were that HIF-1α mRNA was downregulated in hypoxia (1% oxygen) possibly due
to a simultaneous upregulation of a natural antisense to HIF-1α, aHIF. HIF-2α was also
shown to be negatively regulated by hypoxia at the mRNA level but the mechanisms behind
this were not uncovered in the present study. Cytokines induced HIF-1α mRNA, protein and
activity but reduced levels of HIF-2α mRNA. The description of regulation of HIF-1α by
cytokines such as tumour necrosis factor α, supports the concept that HIF transcription factors
may represent a key convergence point in RA for hypoxia and cytokines.
In addition to studying the regulation of HIFs by inflammatory cytokines and
hypoxia, 84 angiogenic genes were investigated for their hypoxia-responsiveness in RA FLS
by PCR array screening. Two genes, angiopoietin-like 4 (ANGPTL-4) and leptin, were
strongly induced in response to hypoxia in RA FLS in comparison to cells grown in normoxia
(21% oxygen). Small interfering RNA technology was used to transiently knock-down HIF-
1α and/or HIF-2α which demonstrated that the hypoxia-inducibility of both ANGPTL-4 and
leptin was dependent on HIFs, but that ANGPTL-4 induction was mainly HIF-1α dependent,
compared to leptin which seemed to be regulated predominantly by HIF-2α. The secretion of
leptin was measured by ELISA, and the functional significance of RA FLS-derived leptin in
angiogenesis was further investigated using ELISAs and an MTT assay. As leptin has been
reported to be elevated in the serum and synovial fluid of RA patients, leptin may represent a
future target for anti-angiogenic therapy in RA.
The research described in this thesis aimed to gain a better understanding of how
HIFs are regulated by hypoxia and cytokines in RA FLS, using FLS grown from total
dissociated human RA synovial membranes, and hereby to understand what governs the
production of angiogenic factors in the RA synovial milieu
Development of a novel real-time qPCR assay for the dual detection of canine and phocine distemper virus
Kan vedtak om etablering av kampflybase snu de dystre utsiktene for Evenes kommune?
Master i Human Resource Management - Nord universitet 202
Long weekly working hours and ischaemic heart disease:a follow-up study among 145 861 randomly selected workers in Denmark
Når helsepersonell er straffeforfulgt for seksuelle overgrep begått utenfor yrkesutøvelsen. - Hvordan helsepersonell som er straffeforfulgt for seksuelle overgrep, er egnet til å yte helsehjelp. Med særlig søkelys på helsepersonelloven §§ 20 a, 57, 59 og 62.
MasteroppgaveJUS399MAJUR-2MAJU
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