TNF binding to TNFR1 leads to the recruitment of TRADD, TRAF2 and RIP, forming complex I'

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TNF-R1-induced signaling pathways via complexes I
and II

• TNF binding to TNF-R1 leads to the recruitment
  of TRADD, TRAF2 and RIP, forming complex I.
• Signaling from complex I leads to NF-?B
  activation via activation of the IKK complex.
• The IKKß catalytic subunit of the IKK complex
  phosphorylates the NF-?B-bound I?Ba, leading to
  its ubiquitination and subsequent proteasomal
  degradation.
• This allows NF-?B to translocate to the nucleus,
  where it induces the transcription of genes with
  an NF-?B consensus site in their promoter region.
  
• In addition, signaling from complex I activates
  the p38, ERK and JNK MAP kinases.
• Recruitment of FADD and procaspase-8 results in
  the formation of the cytosolic complex II, where
  caspase-8 is activated.
• Caspase-8 initiates the mitochondrial pathway by
  cleaving Bid to tBid, which induces mitochondrial
  permeabilization that results in the release of
  cytochrome c. This initiates an amplification
  loop that results in full-blown caspase activity
  and subsequent apoptosis.

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TNF binding to TNF-R1 leads to activation of
JNK1, which phosphorylates the ubiquitin ligase
Itch. Activated Itch then ubiquitinates c-FLIP,
which is bound to FADD and thereby prevents
recruitment of procaspase-8 to complex II. This
leads to proteasomal degradation of c-FLIP,
allowing the proper assembly of complex II and
subsequent signaling to apoptosis.
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Arthritis Inflammation of the joints
Diseases RA, OA, lupus, scleroderma, psoriatic
arthritis, ankylosing spondylitis Population
. over 4 million Canadians afflicted with
arthritis and other autoimmune diseases .
2/3 are women . 3/5 are younger than 65 .
by 2026 estimate will be 6 million . cost is
4.4 billion annually . overall economic
burden consumes 10.35 of all illnesses,
yet only 1.3 of health research dollars
Drugs NSAIDS (Nonsteroidal anti-inflammatory
drugs) DMARDS (disease modifying
anti-rheumatic drugs)
(Cox-2 inhibitors) Celebrex, Vioxx, Voltaren
(biologicals) Etanercept, Infliximab,

Adalimumab, Rituximab
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Rheumatoid Arthritis

• Persistent inflammation
• Bone and cartilage destruction
• Progressive

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Rheumatoid Arthritis
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Rheumatoid Arthritis
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Osteoarthritis
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Disequilibrium of cytokines in joints of patients
with RA
IL-1ra
IL-10
OPG
sTNFR
IL-1
OPGL
TNF-a
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TNF Inhibitors A Molecular Comparison