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Tumor Necrosis Factor- from Macrophages Enhances LPS-Induced Clara Cell Expression of Keratinocyte-Derived Chemokine

¹ Division of Allergy and Pulmonary Medicine, Department of Pediatrics, and ² Division of Pulmonary and Critical Care Medicine, Department of Medicine, and ³ Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri; and ⁴ Department of Pathology, Phoenix Children's Hospital, Phoenix, Arizona

Correspondence and requests for reprints should be addressed to Robert M. Senior, Department of Medicine, Washington University School of Medicine, 902 Yalem, Box 8052, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail: rsenior{at}im.wustl.edu

Tumor necrosis factor (TNF)- is a cytokine produced by alveolar macrophages in response to LPS in the lung. Clara cells are bronchiolar epithelial cells that produce a variety of proinflammatory cytokines in response to LPS but not to TNF-. In this study, we examined whether TNF- affects Clara cell cytokine production in the setting of LPS stimulation. Using a transformed murine Clara cell line (C22), we observed that both LPS and TNF- induced production of keratinocyte-derived chemokine (KC) and monocyte chemoattractant protein (MCP)-1. We also found that simultaneous LPS and TNF- stimulation is synergistic for KC production, but additive for MCP-1 production. By using a Transwell coculture system of RAW264.7 macrophages and Clara cells isolated from C57Bl/6 mice, we found that macrophages produce a soluble factor that enhances Clara cell KC production in response to LPS. Cocultures of Clara cells from mice deficient in TNF- receptors with RAW264.7 macrophages demonstrated that the effect of macrophages on Clara cells is mediated primarily via TNF-. To determine whether these findings occur in vivo, we treated wild-type and TNF receptor–deficient mice intratracheally with LPS and examined the expression of KC. LPS-treated, TNF receptor–deficient mice showed much less KC mRNA in airway epithelial cells compared with wild-type mice. In contrast, a similar number of KC-expressing cells was seen in the lung periphery. Thus, upregulation of KC by Clara cells in the setting of LPS stimulation is largely dependent on TNF- originating from alveolar macrophages. These findings shed light on macrophage–Clara cell interactions in regulating the pulmonary inflammatory response to LPS.

Key Words: airway • tumor necrosis factor- • synergism • macrophages

CLINICAL RELEVANCE This research provides new information about interactions between inflammatory cells in the lung and airway epithelial cells. Understanding these interactions will help in the development of new strategies for controlling pulmonary inflammation.