Interleukin-31 and oncostatin-M mediate distinct signaling reactions and response patterns in lung epithelial cells.
Lung epithelial cells are primary targets of oncostatin M (OSM) and, to a lower degree, of interleukin (IL)-6 and IL-31, all members of the IL-6 cytokine family. The OSM receptor (OSMR) signals through activation of STAT and mitogen-activated protein kinase pathways to induce genes encoding differentiated cell functions, reduce cell-cell interaction, and suppress cell proliferation. IL-31 functions through the heteromeric IL-31 receptor, which shares with OSMR the OSMRbeta subunit, but does not engage gp130, the common subunit of all other IL-6 cytokine receptors. Because the response of epithelial cells to IL-31 is unknown, the action of IL-31 was characterized in the human alveolar epithelial cell line A549 in which the expression of the ligand-binding IL-31Ralpha subunit was increased. IL-31 initiated signaling that differed from other IL-6 cytokines by the particularly strong recruitment of the STAT3, ERK, JNK, and Akt pathways. IL-31 was highly effective in suppressing proliferation by altering expression of cell cycle proteins, including up-regulation of p27(Kip1) and down-regulation of cyclin B1, CDC2, CDK6, MCM4, and retinoblastoma. A single STAT3 recruitment site (Tyr-721) in the cytoplasmic domain of IL-31Ralpha exerts a dominant function in the entire receptor complex and is critical for gene induction, morphological changes, and growth inhibition. The data suggest that inflammatory and immune reactions involving activated T-cells regulate functions of epithelial cells by IL-6 cytokines through receptor-defined signaling reactions.
Chattopadhyay
Souvik
S
Department of Molecular and Cellular Biology and Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Tracy
Erin
E
Liang
Ping
P
Robledo
Olivier
O
Rose-John
Stefan
S
Baumann
Heinz
H
D001932:Brain Neoplasms; D045744:Cell Line, Tumor; D016207:Cytokines / Q000502:physiology; D017930:Genes, Reporter; D005910:Glioma; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000502:physiology; D007378:Interleukins / Q000494:pharmacology*; D008168:Lung / Q000276:immunology / Q000502:physiology*; D009447:Neuroblastoma; D009836:Oligodendroglia; D053683:Oncostatin M / Q000494:pharmacology*; D018123:Receptors, Interleukin / Q000235:genetics / Q000502:physiology; D053677:Receptors, Oncostatin M / Q000235:genetics / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D020545:Respiratory Mucosa / Q000276:immunology / Q000502:physiology*; D014162:Transfection
D016207:Cytokines; C502187:IL31 protein, human; C502188:IL31RA protein, human; D015850:Interleukin-6; D007378:Interleukins; D018123:Receptors, Interleukin; D053677:Receptors, Oncostatin M; D011994:Recombinant Proteins; D053683:Oncostatin M