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J Biol Chem. 2015 Feb 13;290(7):4528-36. doi: 10.1074/jbc.M114.627786. Epub 2015 Jan 2.

Structure-function analysis of CCL28 in the development of post-viral asthma.

Author information

1
From the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226 and.
2
Department of Pediatrics, Section of Allergy and Immunology, Medical College of Wisconsin, Milwaukee, Milwaukee 53226.
3
Department of Pediatrics, Section of Allergy and Immunology, Medical College of Wisconsin, Milwaukee, Milwaukee 53226 wheeze@allergist.com.
4
From the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226 and bvolkman@mcw.edu.

Abstract

CCL28 is a human chemokine constitutively expressed by epithelial cells in diverse mucosal tissues and is known to attract a variety of immune cell types including T-cell subsets and eosinophils. Elevated levels of CCL28 have been found in the airways of individuals with asthma, and previous studies have indicated that CCL28 plays a vital role in the acute development of post-viral asthma. Our study builds on this, demonstrating that CCL28 is also important in the chronic post-viral asthma phenotype. In the absence of a viral infection, we also demonstrate that CCL28 is both necessary and sufficient for induction of asthma pathology. Additionally, we present the first effort aimed at elucidating the structural features of CCL28. Chemokines are defined by a conserved tertiary structure composed of a three-stranded β-sheet and a C-terminal α-helix constrained by two disulfide bonds. In addition to the four disulfide bond-forming cysteine residues that define the traditional chemokine fold, CCL28 possesses two additional cysteine residues that form a third disulfide bond. If all disulfide bonds are disrupted, recombinant human CCL28 is no longer able to drive mouse CD4+ T-cell chemotaxis or in vivo airway hyper-reactivity, indicating that the conserved chemokine fold is necessary for its biologic activity. Due to the intimate relationship between CCL28 and asthma pathology, it is clear that CCL28 presents a novel target for the development of alternative asthma therapeutics.

KEYWORDS:

Asthma; Chemokine; Disulfide; Mass Spectrometry (MS); Nuclear Magnetic Resonance (NMR); Protein Structure

PMID:
25556652
PMCID:
PMC4326855
DOI:
10.1074/jbc.M114.627786
[Indexed for MEDLINE]
Free PMC Article

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