Enbrel may act to reduce inflammation through inhibition of NF-kappaB

Etanercept (Enbrel) inhibits NF-kappaB when used in the treatment of psoriatic arthritis

The immune system is extremely complex and includes many feedback loops (positive and negative) as well as much ‘cross talk’ between its various components.

The relationship between NF-kB and TNF is defined (in part) by a positive feedback loop.

NF-kB activation increases TNF production. TNF activates NF-kB.

TNF => NF-kB activation => TNF production => More NF-kB activation => More TNF, etc.  Enbrel breaks what seems to have become a pathological feedback loop.

From the Enbrel website:

ENBREL is a type of protein called a tumor necrosis factor (TNF) blocker that blocks the action of a substance your body makes called TNF. Tumor necrosis factor is made by your body’s immune system. People with immune diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis have too much TNF in their bodies.

Of course the feedback loop does not always result in pathology. The body normally has some means by which to prevent inflammation constantly getting out of hand.

Why do people with the above conditions have too much TNF in their bodies?

The publication:

January, 2008

Activation of nuclear factor kappa B and mitogen activated protein kinases in psoriatic arthritis before and after etanercept treatment.

Summary of the abstract

OBJECTIVE: To study activation of intracellular pathways depending on nuclear factor kappa B (NFkappaB) and mitogen activated kinases (MAPK) in the synovium of patients with psoriatic arthritis before and after treatment with etanercept.

METHODS: Synovial biopsies were obtained by needle arthroscopy of the knee in 9 patients with active psoriatic arthritis before the initiation of etanercept. Follow-up biopsies were taken in the same knee after 6 months.

RESULTS: Histological severity scores were significantly reduced after etanercept treatment.

CONCLUSIONS: Etanercept therapy resulted in a significant decrease in NFkappaB, JNK and ERK, but not in p38 activation. Persistent activation of these pathways, albeit reduced, may trigger positive feedback loops and flares of arthritis after cessation of etanercept.

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