Oncostatin M causes eotaxin-1 release from airway smooth muscle: synergy with IL-4 and IL-13.

Faffe DS, Flynt L, Mellema M, Moore PE, Silverman ES, Subramaniam V, Jones MR, Mizgerd JP, Whitehead T, Imrich A, Panettieri RA, Shore SA
J Allergy Clin Immunol. 2005 115 (3): 514-20

PMID: 15753898 · DOI:10.1016/j.jaci.2004.11.033

BACKGROUND - Eotaxin is implicated in asthmatic eosinophilia. Oncostatin M (OSM) causes eotaxin release from fibroblasts.

OBJECTIVE - We sought to examine the effects and mechanism of action of OSM and other IL-6 family cytokines on eotaxin release from human airway smooth muscle cells.

METHODS - Eotaxin 1 release was measured by means of ELISA. Western blotting was used to examine mitogen-activated protein kinase and signal transducer and activator of transcription 3 (STAT-3) phosphorylation. Eotaxin promoter activity was analyzed in cells transfected with wild-type STAT-3, a mutant form of STAT-3 that cannot be phosphorylated, and a constitutively active form of STAT-3. The mRNA and protein expression of IL-4R alpha, the signaling receptor for IL-4 and IL-13, was evaluated by means of real-time PCR and flow cytometry, respectively.

RESULTS - OSM increased eotaxin 1 release and augmented IL-4- or IL-13-induced eotaxin release, whereas other IL-6 family cytokines did not. OSM caused a greater increase in STAT-3 phosphorylation and STAT-3-mediated gene transcription than other IL-6 family cytokines. OSM increased eotaxin promoter activity and augmented IL-13- and IL-4-induced increases in promoter activity. The constitutively active form of STAT-3 increased eotaxin promoter activity, whereas the mutant form of STAT-3 that cannot be phosphorylated significantly reduced eotaxin promoter activity induced by OSM or IL-4 plus OSM. OSM increased IL-4R alpha mRNA and protein levels.

CONCLUSIONS - OSM induces eotaxin 1 expression in human airway smooth muscle cells by a mechanism involving STAT-3. OSM synergizes with IL-13 and IL-4 to increase eotaxin 1 expression, possibly as a result of effects on IL-4R alpha expression.

MeSH Terms (22)

Blotting, Western Chemokine CCL11 Chemokines, CC DNA-Binding Proteins Drug Synergism Enzyme-Linked Immunosorbent Assay Flow Cytometry Growth Inhibitors Humans Interleukin-4 Interleukin-13 Lung Mitogen-Activated Protein Kinases Muscle, Smooth Oncostatin M Peptides Phosphorylation Receptors, Interleukin-4 Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger STAT3 Transcription Factor Trans-Activators

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