Xx50225 Antichronic Inflammation

L2 – Therapy rationale
Therapies
NSAIDS eg aspirin, ibruprofen
DMARDS e.g. methotrexate, leflunomide
STEROIDS e.g prednisolone
BIOLOGICALS e.g infliximab, adalimumab
Why do we use them?
How/ why do they have an effect?

Current therapies
3
4
Endogenous Corticoids
Released from adrenal cortex
Mineralocorticoids - aldosterone
– affect water and electrolyte balance
Glucocorticoids - hydrocortisone and corticosterone
- affect carbohydrate and protein metabolism

- anti inflammatory and immunosuppressive effects
The HPA axis *
Pro-inflammatory cytokines
(IL-1, IL-6, TNF-)
Corticotrophin Releasing Hormone
AdrenoCorticoTrophic Hormone
Anti inflammatory effects
• Inhibit both early and late stages of inflammatory
response
• Decrease extravasation
• Inhibit cell activation
• Decrease production of inflammatory mediators

Mechanism of Action
Glucocorticoids enter cells and bind to cytoplasmic receptors.
Complex translocates to the nucleus to act as transcription factor
Can bind to response elements and activate gene transcription
Can bind and repress gene activation
Can interact and inhibit binding of other transcription factors

(AP-1 and NFB)
Metabolic side effects
Osteoporosis
(dec – coll syn, osteoblast func, Ca absorption by inh of

vitD action ) (Parathyroid hormone then increases Ca
resorption from bone)
Diabetogenic plus increased appetite – obesity
Mineralocortocoid effects –Na/ H2O retention,

hypertension, oedema and CV events
Toxicity of corticosteroids
Many unwanted side-effects associated with GC actions
Generally associated with high doses, systemic long-term admin
Immunosuppression can increase risk of infections
Impaired leucocyte traffic can delay wound healing
Suppress HPA axis through feedback inhibition

Cytokines- TNF and IL-1
Proinflammatory cytokines involved in cell proliferation (both)
and apoptosis (TNF) (activate NFkB)
Primary function is beneficial activation of innate immune

system
Excess or inappropriate release causes inflammation, tissue

destruction and organ damage
Both produced by LPS-activated monocytes/ macrophages
Can regulate each other

Interleukin-1 activation
2 forms  and 
– IL-1 mainly cytosolic or membrane bound,
-  most common circulating form
No leader sequence – synthesised in microtubules not ER
Synthesised as precursors and cleaved by Interleukin-1 Converting

Enzyme (ICE), also known as caspase 1
ICE Inhibitors are anti inflammatory agents
Release facilitated by ATP receptor P2X7

Soluble IL-1
P2XR +
ICE
ProICE
MICROTUBULE
ER
IL-1 Effects
High conc enter blood and cause fever
Increases synthesis of COX-2 and iNOS
Increases expression of VCAM and ICAM
Increases bone erosion (osteoclasts, RANKL)
Doesn’t induce apoptosis or septic shock

Interleukin-1 receptors
sIL-1RII
sIL-1RI
Accessory
Protein
Type II IL-1 R
decoy
Type I IL-1R
TRAF
IRAK
Activation
NFB and AP-1
Role for IL-1 in RA
First suggested by Krane and Dayer
IL-1 infusion in animals caused inflammation
IL-1 inhibitors reduce disease
High circulating levels of IL-1 in patients
Causes many symptoms due to its induction of

PGs and collagenase
TNF
First identified in 1970s as substance causing haemorrhagic
necrosis of solid tumours
Part of a superfamily of cytokines which includes TNF,

Lymphotoxin (TNF), Fas-L and CD40L
Most are membrane-associated homotrimers which bind

trimeric receptors
Functional effects often due to upregulation of other cytokines

(IL-1,2,4,6,10,12,18, APP,LTs<PGs<NO and O2 free radicals)
TNF production
Bac, viruses, TNF, IL-1 and 2 all increase mRNA but not
necessarily protein
LPS increases both by stabilisation of mRNA
Synthesised as non glycosylated membrane bound protein

(C terminal extracellular)
Can be cleaved from surface by MMPs
Both membrane and soluble forms active and mediate cytotoxic

and inflammatory effects through cell-cell contact
TNF Receptors
2 types - present on all cells except rbc, II-inducible. Membrane bound
or soluble (MMP cleavage)
TNFRI 55kDa recruits caspases –apoptosis

TRAFs – gene transcription (NFkB, AP-1)
TNFRII 75kDa recruits TRAFs – gene transcription
Molecular switch to determine death or activation
In T cells high levels of RIP triggered apoptosis, low levels induced

activation
TNF Receptors and Ligand
sTNF
sTNFRI
MMP cleavage
TNF Effects
Stimulates recruitment of neutrophils and monocytes to site
of infection and their activation
- Increases expression of adhesion molecules on EC

Stimulates EC and mac to secrete chemokines
- Stimulates mononuclear phagocytes to synthesise IL-1
In severe cases, large quantities released into bloodstream

- Acts on hypothalamus to induce fever (PGs)
- Induces hepatocytes to increase release of APP
- Prolonged exposure - muscle wasting, inhibition cardiac
contractility, intravascular thrombosis (Septic Shock)
Key points
Cytokines are the main mediators of chronic inflammation
TNF is the prototype of proinflammatory cytokines
These pathways can lead to cellular proliferation or cellular death
TNF effects induce the symptoms of inflammation

-Vascular leakage
-Cellular infiltration
-Tissue damage
Acute, controlled release of TNF is GOOD,
prolonged or high levels are BAD

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L2 – Therapy rationale

NSAIDS eg aspirin, ibruprofen

DMARDS e.g. methotrexate, leflunomide

STEROIDS e.g prednisolone

BIOLOGICALS e.g infliximab, adalimumab

Why do we use them?

How/ why do they have an effect?

Glucocorticoids - hydrocortisone and corticosterone

- affect carbohydrate and protein metabolism

Corticotrophin Releasing Hormone

• Inhibit cell activation

• Decrease production of inflammatory mediators

Complex translocates to the nucleus to act as transcription factor

Can bind to response elements and activate gene transcription

Can bind and repress gene activation

Can interact and inhibit binding of other transcription factors

(dec – coll syn, osteoblast func, Ca absorption by inh of

Diabetogenic plus increased appetite – obesity

Mineralocortocoid effects –Na/ H2O retention,

Generally associated with high doses, systemic long-term admin

Immunosuppression can increase risk of infections

Impaired leucocyte traffic can delay wound healing

Suppress HPA axis through feedback inhibition

Primary function is beneficial activation of innate immune

Excess or inappropriate release causes inflammation, tissue

Both produced by LPS-activated monocytes/ macrophages

Can regulate each other

-  most common circulating form

No leader sequence – synthesised in microtubules not ER

Synthesised as precursors and cleaved by Interleukin-1 Converting

ICE Inhibitors are anti inflammatory agents

Release facilitated by ATP receptor P2X7

High conc enter blood and cause fever

Increases synthesis of COX-2 and iNOS

Increases expression of VCAM and ICAM

Increases bone erosion (osteoclasts, RANKL)

Doesn’t induce apoptosis or septic shock

IL-1 infusion in animals caused inflammation

IL-1 inhibitors reduce disease

High circulating levels of IL-1 in patients

Causes many symptoms due to its induction of

Part of a superfamily of cytokines which includes TNF,

Most are membrane-associated homotrimers which bind

Functional effects often due to upregulation of other cytokines

LPS increases both by stabilisation of mRNA

Synthesised as non glycosylated membrane bound protein

Can be cleaved from surface by MMPs

Both membrane and soluble forms active and mediate cytotoxic

TNFRI 55kDa recruits caspases –apoptosis

TNFRII 75kDa recruits TRAFs – gene transcription

Molecular switch to determine death or activation

In T cells high levels of RIP triggered apoptosis, low levels induced

- Increases expression of adhesion molecules on EC

In severe cases, large quantities released into bloodstream

TNF is the prototype of proinflammatory cytokines

These pathways can lead to cellular proliferation or cellular death

TNF effects induce the symptoms of inflammation

Acute, controlled release of TNF is GOOD,

prolonged or high levels are BAD

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