Progress in Chemokine-Like Factor 1 Research over the Past 10 Years: From Promoting Inflammatory Cell Trafficking to Inhibiting Allergic Airway Inflammation

Abstract

Chemokine-like factor 1 (CKLF1) is a cytokine, first described in 2001. CKLF1 is highly expressed in the lung and leukocytes. Recombinant CKLF1 has chemotactic activity on leukocytes, and stimulates the proliferation of murine skeletal muscle cells. Administration of CKLF1 in mice caused dramatic pathological changes in the lungs, including peribronchial leukocyte infiltration, epithelial shedding, collagen deposition, and proliferation of bronchial smooth muscle cells. Expression of CKLF1 mRNA in PBMCs and CKLF1 immunoreactivity in bronchial mucosa were found to be higher in an asthmatic group than in controls. A CKLF1-specific monoclonal antibody was generated using an intramuscular injection of pCDI-CKLF1 followed by electroporation in vivo, instead of a conventional protein immunization strategy. CCR4 is a functional receptor for CKLF1; this was confirmed using a chemotaxis assay, calcium flux assays, and receptor internalization. Two peptides from secreted CKLF1 in cell supernatants were obtained when recombinant CKLF1 was stably expressed in Drosophila S2 cells, termed CKLF1-C27 (C27) and CKLF1-C19 (C19). C27 and C19 had the same effect through CCR4 as the recombinant CKLF1 protein. Although with weaker chemotactic activity, C19 can inhibit chemotaxis induced by other chemokines, such as CKLF1 and TARC/CCL17. Chemically synthesized C19 peptide was injected intraperitoneally to inhibit allergic inflammation associated with asthma in mice, resulting in a significant reduction in AHR, airway eosinophilia, and the number of lymphocytes in BALF. Most recently, C19 peptide was used to treat murine allergic rhinitis. Intranasal administration of C19 reduced allergic symptoms, such as sneezing and rubbing, and serum concentrations of IgE. Mice treated with C19 or budesonide, a intranasal glucocorticoid steroid for the treatment of non-infectious rhinitis, for the treatment of non-infectious rhinitis, showed fewer eosinophils in the submucosa or peribronchiolar zone, while the nasal mucosa of untreated allergic mice displayed significant increases in eosinophils and conspicuous hyperplasia of the mucous glands