CCR2 and CXCR3 agonistic chemokines are differently expressed and regulated in human alveolar epithelial cells type II.
The attraction of leukocytes from circulation to inflamed lungs depends on the activation of both the leukocytes and the resident cells within the lung. In this study we determined gene expression and secretion patterns for monocyte chemoattractant protein-1 (MCP-1/CCL2) and T-cell specific CXCR3 agonistic chemokines (Mig/CXCL9, IP-10/CXCL10, and I-TAC/CXCL11) in TNF-alpha-, IFN-gamma-, and IL-1beta-stimulated human alveolar epithelial cells type II (AEC-II). AEC-II constitutively expressed high level of CCL2 mRNA in vitro and in situ , and released CCL2 protein in vitro . Treatment of AEC-II with proinflammatory cytokines up-regulated both CCL2 mRNA expression and release of immunoreactive CCL2, whereas IFN-gamma had no effect on CCL2 release. In contrast, CXCR3 agonistic chemokines were not detected in freshly isolated AEC-II or in non-stimulated epithelial like cell line A549. IFN-gamma, alone or in combination with IL-1beta and TNF-alpha resulted in an increase in CXCL10, CXCL11, and CXCL9 mRNA expression and generation of CXCL10 protein by AEC-II or A549 cells. CXCL10 gene expression and secretion were induced in dose-dependent manner after cytokine-stimulation of AEC-II with an order of potency IFN-gamma > > IL-1beta > or = TNF-alpha. Additionally, we localized the CCL2 and CXCL10 mRNAs in human lung tissue explants by in situ hybridization, and demonstrated the selective effects of cytokines and dexamethasone on CCL2 and CXCL10 expression. These data suggest that the regulation of the CCL2 and CXCL10 expression exhibit significant differences in their mechanisms, and also demonstrate that the alveolar epithelium contributes to the cytokine milieu of the lung, with the ability to respond to locally generated cytokines and to produce potent mediators of the local inflammatory response.
Pechkovsky
Dmitri V
DV
Department of Pneumology, Medical Center, Albert-Ludwigs University, Freiburg, Germany. dpech@tut.by
Goldmann
Torsten
T
Ludwig
Corinna
C
Prasse
Antje
A
Vollmer
Ekkehard
E
Müller-Quernheim
Joachim
J
Zissel
Gernot
G
D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D011650:Pulmonary Alveoli / Q000378:metabolism*; D054390:Receptors, CCR2; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000819:agonists / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism*; D014018:Tissue Distribution
C515334:CCR2 protein, human; C515187:CXCR3 protein, human; D018925:Chemokines; D054390:Receptors, CCR2; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine