Faculty Collaboration Database

Structure-function analysis of CCL28 in the development of post-viral asthma. J Biol Chem 2015 Feb 13;290(7):4528-36

Date

01/06/2015

Pubmed ID

25556652

Pubmed Central ID

PMC4326855

DOI

10.1074/jbc.M114.627786

Scopus ID

2-s2.0-84922787785 (requires institutional sign-in at Scopus site)   18 Citations

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.

Author List

Thomas MA, Buelow BJ, Nevins AM, Jones SE, Peterson FC, Gundry RL, Grayson MH, Volkman BF

Authors

Becky J. Buelow MD Associate Professor in the Pediatrics department at Medical College of Wisconsin
Francis C. Peterson PhD Professor in the Biochemistry department at Medical College of Wisconsin
Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Animals
Asthma
CD4-Positive T-Lymphocytes
Chemokines, CC
Chemotaxis
Chronic Disease
Epithelial Cells
Humans
Magnetic Resonance Spectroscopy
Male
Mice
Mice, Inbred C57BL
Molecular Sequence Data
Protein Conformation
Respirovirus Infections
Sendai virus
Sequence Homology, Amino Acid
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Structure-Activity Relationship
T-Lymphocyte Subsets