Interleukin-4 (IL-4)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Source: CD4 T cells (TH2), mast cells.

The 3 established T(H)2 cytokines, IL-4, IL-5, and IL-13, each play a nonredundant role in allergic disease pathology.

Receptors: Type I cytokine receptor family which signals through the Jak-STAT pathway (STAT6). Receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 contain γ chain, which is affected in X-linked SCID.

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IL-4 effects

- B cells: isotype switching to IgE
- T cells: TH2 differentiation, proliferation
- Macrophages: inhibition of IFN-gamma-mediated activation
- Mast cells: proliferation (in vitro)

IL-4 is the key cytokine for the IgE isotype switch.

Induction of VCAM -1, promotion of eosinophil migration, mucus production.

Th2 lymphocyte differentiation with subsequent release of additional IL-4, IL-5, and IL-13.

IL-4 and GATA3

IL-4 activates STAT6, which then engages the transcription factor GATA3, leading to secretion of IL-4. GATA3 is pivotal for Th2 maturation.

T-bet (also called TBX21 or T-box 21) is pivotal for Th1 maturation. T-bet inhibits IL-4, IL-5, and IL-17 secretion. T-bet may also inhibit Th2 differentiation by preventing GATA3 from interacting with its target DNA. T-bet is a bridge between innate and adaptive immunity (

Oral synthesis inhibitors of IL-4

Suplatast tosilate inhibits the production of IL-4 and IL-5. In a study of asthmatic patients, there was an improvement in airway hyperresponsiveness, symptoms, and PEFR, and decreased IgE.

Soluble IL-4 receptor

Altrakincept is a recombinant, human IL-4 receptor - the extracellular portion. A small proof-of-concept trials of inhaled altrakincept in asthma showed promise but 2 larger trials failed to confirm efficacy - did not invalidate IL-4 as a target - there were concerns over the bioavailability of altrakincept in those trials.

IL-4Ra receptor antagonist (antibody)

AMG-317 is a fully human mAb antagonist to the IL-4Ra receptor - inhibits both IL-4 and IL-13 signaling). Developed by Amgen (hence the name "AMG") for treatment of allergic asthma.

AMG-317 (AAAAI abstract, March 09): 12-wk RCT, double-blind, 260 subjects with uncontrolled asthma, FEV1 50-80%. Randomized to 12 weekly injections of AMG 317 (75mg, 150mg, 300mg) or placebo. Primary endpoint was improvement in ACQ score.

At week 12, mean improvements in ACQ scores were: placebo (0.48), AMG 317 75mg (0.33), 150mg (0.56), and 300mg (0.65) (p=NS for all). Median improvement in total serum IgE was significantly greater in the 300mg AMG 317 group vs placebo. No AMG 317 treatment-related SAEs were reported.

Aerovant INH and Aeroderm IV

IL-4 mutein that inhibits the effects of both IL-4 and IL-13 through its ability to block IL-4Ra.

Aerovant (Pitrakinra) INH

Aerovant INH: Phase IIa, 30-patient study met its primary endpoint of reducing the severity of late asthmatic response by 72% percent (p lower than 0.001), BID for 27 days. Started in 2009: Phase IIb clinical trial of inhaled dry powder Aerovant in patients with uncontrolled asthma.

Aeroderm IV

PEGylated recombinant human IL-4 variant, block IL-4Ra.

Phase Iia in 24 patients with atopic dermatitis using a non-PEGylated form of the molecule (AER 001). Future studies will be in severe atopic eczema patients using the PEGylated form (AER 003).


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Published: 04/09/2010
Updated: 08/09/2010

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