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* Lung Cell Biology, Section of Airways Disease, National Heart and Lung Institute, Imperial College, London, United Kingdom;
Department of Pharmacology and Therapeutics, Institute of Infection, Immunity and Inflammation, University of Calgary, Calgary, Alberta, Canada;
Department of Thoracic Surgery, Royal Brompton and Harefield National Health Service Trust, London, United Kingdom; and
AstraZeneca R&D, Loughborough, United Kingdom
Bacterial colonization is a secondary feature of many lung disorders associated with elevated cytokine levels and increased leukocyte recruitment. We hypothesized that, alongside macrophages, the epithelium would be an important source of these mediators. We investigated the effect of LPS (0, 10, 100, and 1000 ng/ml LPS, up to 24 h) on primary human lung macrophages and alveolar type II epithelial cells (ATII; isolated from resected lung tissue). Although macrophages produced higher levels of the cytokines TNF-
and IL-1
(p < 0.0001), ATII cells produced higher levels of chemokines MCP-1, IL-8, and growth-related oncogene (p < 0.001), in a time- and concentration-dependent manner. Macrophage (but not ATII cell) responses to LPS required activation of ERK1/2 and p38 MAPK signaling cascades; phosphorylated ERK1/2 was constitutively up-regulated in ATII cells. Blocking Abs to TNF- and IL-1 during LPS exposure showed that ATII cell (not macrophage) MCP-1 release depended on the autocrine effects of IL-1 and TNF- (p < 0.003, 24 h). ATII cell release of IL-6 depended on autocrine effects of TNF- (p < 0.006, 24 h). Macrophage IL-6 release was most effectively inhibited when both TNF- and IL-1 were blocked (p < 0.03, 24 h). Conditioned media from ATII cells stimulated more leukocyte migration in vitro than conditioned media from macrophages (p < 0.0002). These results show differential activation of cytokine and chemokine release by ATII cells and macrophages following LPS exposure. Activated alveolar epithelium is an important source of chemokines that orchestrate leukocyte migration to the peripheral lung; early release of TNF- and IL-1 by stimulated macrophages may contribute to alveolar epithelial cell activation and chemokine production.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 A.J.T. and P.A.F. were supported by a grant from AstraZeneca.
2 Address correspondence and reprint requests to Dr. Teresa D. Tetley, Lung Cell Biology, Section of Airways Disease, National Heart and Lung Institute, Imperial College, London, U.K. SW3 6LY. E-mail address: t.tetley{at}imperial.ac.uk
3 Abbreviations used in this paper: COPD, chronic obstructive pulmonary disease; ATII, alveolar epithelial type II; GRO, growth-related oncogene; PSG, penicillin/streptomycin/glutamine; KO, knockout.
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