Soluble IL-6 receptor in pediatric severe asthma: relationship to asthma control and interaction with race Pubblico

Abstract

Introduction: Asthma affects up to 10% of all children in the U.S. A subset of these children has severe or refractory asthma, characterized by continuing symptoms despite maximal therapy with corticosteroids. Increased inflammation has been shown molecularly in children with severe asthma, including as one of many markers, increased IL-6. A recent development is the discovery of the soluble IL-6 receptor (sIL-6R) which, unlike the membrane-bound receptor, is found throughout the body and may be responsible for the action of IL-6 in the lung. We hypothesized that plasma IL-6 and sIL-6R expression would be increased in children with severe asthma vs. mild-to-moderate asthma. We then formed a data-driven hypothesis that sIL-6R expression is related to asthma control (independent of treatment regimen) and that the effect of sIL-6R on asthma control is modified by race. Methods: Banked plasma and extensive characterization data was available for 129 children with asthma enrolled in a previous cohort study. Protein expression of IL-6 was measured using a microsphere-based kit and sIL-6R was measured by ELISA. Results: We found no difference in IL-6 or sIL-6R expression between severe and mild-to-moderate asthmatics classified by the American Thoracic Society (ATS) definition. However, in a logistic model of very poorly controlled (VPC) asthma classified by the NHLBI asthma control definition, sIL-6R expression was a significant predictor among Caucasian children (OR 3.34 for a 10ng/mL increase, 95% CI 1.18-9.43), but not in children of other races (OR 1.33, 95% CI 0.73-2.44). Conclusions: These findings are supported by genetic studies of the asthma susceptibility SNP in the coding region of sIL-6R which has been found in populations of European ancestry. This complex relationship provides a starting point for future research into the genetic basis of asthma susceptibility and poor asthma control with conventional therapies. Future research may eventually lead to novel treatments for corticosteroid-resistant patients.

Table of Contents

TABLE OF CONTENTS

Section Page

Introduction ............................................................. 1

Background .............................................................. 2

IL-6 expression is increased in asthma.............................. 3

Functions of IL-6 in asthma ........................................... 4

Trans signaling may mediate IL-6 action in the lung ............ 5

Soluble IL-6 receptor signaling may be increased in asthma .. 5

IL-6 in pediatric asthma ................................................ 6

Hypothesis and aims .................................................. 8

Methods

Subjects ..................................................................... 9

Subject characterization ............................................... 10

Sample preparation ...................................................... 10

Protein expression .................................................... ... 10

Statistical analysis ....................................................... 11

Results

American Thoracic Society asthma severity analysis .................................. 12

National Heart, Lung, and Blood Institute asthma control analysis ................. 13

Discussion ........................................................................................ 14

References ....................................................................................... 19

Tables and Figures Table A

American Thoracic Society (ATS) definition of severe asthma

24 Table B

National Heart, Lung, and Blood Institute (NHLBI) guidelines asthma control classification

24 Table 1

Characteristics of children with asthma classified as severe or nonsevere based on the American Thoracic Society (ATS) criteria

25 Table 2

Mean sIL-6R expression in children with asthma compared between groups of potential confounding variables

26 Table 3

Characteristics of children with asthma classified by NHLBI asthma control guidelines

27

Table 4

Race specific adjusted odds ratios for very poorly controlled (VPC) asthma vs. well or moderately controlled asthma with a 10ng/mL increase in plasma sIL-6R expression

27

Table 5

Crude and adjusted odds ratios for very poorly controlled (VPC) asthma vs. well or moderately controlled asthma among covariates

28 Figure 1

Plasma IL-6 protein concentration in severe and nonsevere asthma

28 Figure 2

Plasma sIL-6R protein concentration in severe and nonsevere asthma

29 Figure 3

Plasma sgp130 concentration in severe and nonsevere asthma

29 Figure 4

Plasma sIL-6R expression in NHLBI asthma control groups

30 Figure 5

Plasma sIL-6R expression in NHLBI asthma control groups, stratified by race

31

About this Master's Thesis

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School	Laney Graduate School
Department	Clinical Research Curriculum Program
Degree	MS
Submission	Master's Thesis
Language	English
Research Field	Biology, Molecular Biology, Cell
Parola chiave	pediatric soluble IL-6 asthma
Committee Chair / Thesis Advisor	Fitzpatrick, Anne M, Emory University
Committee Members	Bruce, Beau Benjamin, Emory University Klein, Mitchel, Emory University

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