Induction of CXCL5 during inflammation in the rodent lung involves activation of alveolar epithelium.
The lung is continuously exposed to bacteria and their products, and has developed a complex defense mechanism, including neutrophil recruitment. In mice, keratinocyte cell-derived chemokine and macrophage inflammatory protein-2 are the major chemokines for neutrophil recruitment into the lung. We have previously described a role for C-X-C chemokine (CXCL5) in neutrophil trafficking during lipopolysaccharide (LPS)-induced lung inflammation in mice. The aims of the present study were to identify the cellular origin of CXCL5 and to determine the signaling cascades that regulate its expression in the lung during LPS-induced inflammation and in isolated LPS-stimulated CXCL5-expressing cells. Our immunohistochemical analysis indicates that alveolar epithelial type II (AEII) cells are the primary source of CXCL5 in the rodent lung. These in vivo observations were confirmed with primary AEII cells. In addition, our data indicate that the Toll-like receptor 4 (TLR4) signaling cascade involving TLR4, myeloid differentiation factor 88, and Toll-IL-1R domain-containing adapter protein is required to induce CXCL5 expression in the lung. Furthermore, p38 and c-Jun N-terminal kinases are involved in lung CXCL5 expression. Similarly, TLR4, and p38 and c-Jun N-terminal kinases, are associated with LPS-induced CXCL5 expression in AEII cells. These novel observations demonstrate that activation of AEII cells via TLR4-dependent signaling is important for the production of CXCL5 in the lung exposed to LPS.
Jeyaseelan
Samithamby
S
Division of Respiratory Infections, Department of Medicine, National Jewish Medical and Research Center, 1400 Jackson Street Neustadt D-403, Denver, CO 80206, USA. JeyaseelanS@njc.org
Manzer
Rizwan
R
Young
Scott K
SK
Yamamoto
Masahiro
M
Akira
Shizuo
S
Mason
Robert J
RJ
Worthen
G Scott
GS
D000818:Animals; D002478:Cells, Cultured; D054365:Chemokine CXCL5; D019743:Chemokines, CXC / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D016676:Macrophages, Alveolar / Q000166:cytology / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009504:Neutrophils / Q000276:immunology; D011014:Pneumonia / Q000276:immunology* / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011971:Receptors, Immunologic / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4
D054365:Chemokine CXCL5; D019743:Chemokines, CXC; C094739:Cxcl5 protein, mouse; D011971:Receptors, Immunologic; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4