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Signalling

Role of nf-kb signaling in inflammation and

related disordersPresented bySakshi Saxena

ASU2013010200124BSBT 302

IBT-Ivth sem

•Introduction : Inflammation•Physiology of Inflammation•Introduction to Nf-Kb complex•Signaling pathways of Nf-Kb•Role of NF-KB signaling pathway in asthama

Introduction• Inflammation is the body's attempt at self-

protection; the aim being to remove harmful stimuli, including damaged cells, irritants, or pathogens and begin the healing process.

Signs of inflammation• The four cardinal signs of inflammation --the four

"ORs" -- are:• Rubor -- redness. • Tumor -- swelling (puffiness, edema).• Calor -- heat.• Dolor -- pain.

Physiology of Inflammation

Increased tissue perfusion causes redness (rubor), as more red blood cells pass through the tissue.Warmth (calor), as blood carries body heat from the body's core to cooler peripheral tissues.There is normally a balance between fluid leaving vascular spaces and fluid re-entering the system. Inflammation shifts this balance, causing accumulation of interstitial fluid.The fluid build-up which follows this permeability change is called edema and is visible as puffiness or swelling (tumor). Pain and/or itching (dolor) is caused by direct action on nerve endings of the chemical agents released during inflammation.

How is the proteins or theMolecules produced and released

whenInflammation occurs?

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Nf-Kb introduction• NF-κB (nuclear factor kappa-light-chain-enhancer of activated B

cells) is a protein complex that controls transcription of DNA.• In most cells, NF-B complexes are inactive, residing primarily in the

cytoplasm in a complex with any of the family of inhibitory proteins. When the pathway is activated, the inhibitory protein is degraded and the NF-B complex enters the nucleus to modulate target gene expression.

• These factors are involved in the control of a large number of normal cellular and organism processes, such as immune and inflammatory responses, developmental processes, cellular growth, and apoptosis.

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Nf-Kb’s structure• In mammals, the NF-B family is composed of five related transcription

factors: p50, p52, RelA (aka p65), c-Rel and RelB.• These transcription factors are related through an N-terminal DNA-

binding/dimerization domain, called the Rel homology domain, through which they can form homodimers and heterodimers, which bind to a variety of related target DNA sequences called B sites to modulate gene

expression. Rel/Nf-Kb

Class I Class IIRelA, c-Rel and RelB contain C-terminal transcription activation domains (TADs), which enable them to activate target gene expression.

p50 and p52 do not contain C-terminal trans activation domains; therefore, p50 and p52 homodimers can repress transcription.

**Members of this first class are generally not activators of transcription, except when they form dimers with members of the second class

Nf-Kb’s structure

Signaling pathways of Nf-Kb

• Canonical / Classical Pathway Binding of ligand to a cell surface receptor leads to the recruitment of adaptors to the cytoplasmic domain of the receptor .These adaptors in turn recruit I κB kinase (IKK) complex, which phosphorylates I κB and targets it for proteasomal degradation .The IKK complex consists of two catalytically active kinases (IKK and IKK) and a regulatory scaffold protein, NEMO.

IKK and NEMO are required for the activation of complexes such as p50/RelA, p50/c-Rel, etc., whereas IKK is relatively dispensable.

Signaling pathways of Nf-Kb

• Non-Canonical / Alternate Pathway It is responsible for the activation of p100/RelB complexes and occurs during the development of lymphoid organs responsible for the generation of B and T lymphocytes.

This pathway utilizes an IKK complex that comprises two IKKα subunits, but not NEMO.Receptor binding leads to the activation of NIK(nf-kb inducing kinases) which phosphorylates and activates an IKK alpha complex that in turn phosphorylates the IκB domain of p100 leading to the liberation of p52/RelB.

This heterodimer subsequently translocates to the nucleus to activate target genes.

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IkB degradationDiverse functionsResponse to numerous stimulusRapid and transient

No IkB degradation dependentSlow and persistentRespond to specific (TNFR motiff based) signalSpecific functions

ROLE OF NF-KB SIGNALINGIN ASTHMA

• INTRODUCTION Asthma is a chronic lung disease that inflames and narrows the airways.

Asthma causes recurring periods of wheezing (a whistling sound when you breathe), chest tightness, shortness of breath, and coughing.

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• Asthma is associated with the increased expression of several important inflammatory proteins, including cytokines and adhesion molecules.

• Expression of these proteins positively correlates with NF-κB activation in bronchial biopsies from asthmatic patients.

• The increase in these processes involve increased transcription of inflammatory genes that are known to be regulated by transcription factors NF-κB

INVOLVEMENT OF NF-KBIN HYPERACTIVITY

(ASTHMA)

Nf kb gets activated by various stimuli, including cytokines, reactive oxygen species and microorganisms that induce the degradation and release of I-κB from p50 and p65 complex.

INVOLVEMENT OF NF-KBIN HYPERACTIVITY

(ASTHMA)

• It is responsible for airway obstruction and hyper-reactivity. • The histamine involved in this process promote inflammation by

inducing NF-κB activation, which activates genes whose proteins promote inflammation and the maturation of T cells in asthma patients .

INVOLVEMENT OF NF-KBIN INFLAMMATORY RESPONSES

Histamine from allergens

NF-kB activation Signaling pathway Gene activation

Proteins generationInflammation and maturation of T cells

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• The improper functioning of NF-κB in apoptosis leads to recruitment of immune cells which in turn leads to perpetuated inflammatory responses.

• NF-κB stimulates the expression and activity of anti apoptotic protein Bcl-2, while inhibiting apoptotic protein Bax.

• This suggests a progressive decrease in apoptosis and an increase in the survival of lymphocytes that infiltrate the lung of patients with severe asthma.

INVOLVEMENT OF NF-KB IN APOPTOSIS INHIBITIONOF IMMUNE CELLS

Bcl-2Bcl-2

Bax

Bax

Apoptosis

a. Normal cells b. Cells with improper Nf-kB

TREATMENT OF ASTHMA IN RELATION WITH NF-KB SIGNALING

Corticosteroids enter the cell, bind to the glucocorticoid receptor (GR) in the cytoplasm and translocate to the nucleus, where the transcription of target genes is initiated. Many genes contain glucocorticosteroid response elements (GREs) in their promoters. Through transactivation, binding of the activated glucocorticoid receptor homodimer to a GRE in the promoter region of steroid-sensitive genes leads to the transcription of genes encoding anti-inflammatory mediators.

TREATMENT OF ASTHMA IN RELATION WITH NF-KB SIGNALING

Through transrepression, the glucocorticoid receptor–corticosteroid complex interacts with large co-activator molecules with intrinsic histone acetyltransferase (HAT) activity which are activated by pro-inflammatory transcription factors (such as NF-B and AP1), thus switching off expression of the inflammatory genes that are activated by these transcription factors. RNA pol II, RNA polymerase II.

1. “An overview of NF-κB signaling in health and disease” by Claudie Hooper

2. “NF-B and the immune response” ; M S Hayden, A P West and S Ghosh

3. “The Nuclear Factor NF-κB Pathway in Inflammation”; Toby Lawrence4. “Signaling to NF-kappaB” ;Hayden MS, Ghosh S.5. “NF-kB Transcription Factors “;Dr. Thomas Gilmore6. “The involvement of NF-κB Transcription factor in

asthma” Guadalupe Rico-Rosillo ,Gloria Bertha Vega-Robledo

7. Anti-inflammatory actions of corticosteroids.FROM THE ARTICLE:Treatment strategies for allergy and

asthma ; Stephen T. Holgate & Riccardo Polosa

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