What is eotaxin doing in the pleura? Insights into innate immunity from pleural mesothelial cells.

It was appreciated almost 20 years ago that pleural mesothelial cells (PMC) are a biologically active cell type capable of synthesizing a variety of extracellular matrix molecules (1). As such, PMC contribute to the integrity of the pleural membrane, which plays a vital role in facilitating lung expansion and deflation. Research in the past decade has uncovered an additional role for PMC in sensing and responding to signals within the pleural microenvironment. In particular, several recent studies have found that PMC synthesize a diverse array of chemotactic cytokines (or chemokines) in response to distinct extracellular stimuli. This suggests that PMC play an active role in the recruitment of inflammatory cells into the pleural space. Comparable functions have recently been ascribed to other mesodermally-derived cells, including peritoneal mesothelial cells (2). Since the original observation that asbestos-induced pleural neutrophilia involved mesothelial-derived IL-8 production (3, 4), PMC have been shown to secrete both C-C and C-X-C chemokines in different experimental settings (Table 1). Interestingly, Nasreen and coworkers recently reported that PMC secrete IL-8 in a polarized fashion (from basal to apical), which would promote the transmesothelial migration of neutrophils into the pleural cavity (5). The cellular infiltrate in response to a chemokine gradient will depend on the expression of appropriate ligands on, and the state of, activation of target cells. Several recent reviews are available for this active area of research (6, 7). In general, the PMC-derived chemokines described to date can help explain the pleural neutrophilia or monocytosis that accompany different disease states. Thus, the concentration of IL-8 is increased in pleural diseases characterized by neutrophil influx (e.g., complicated parapneumonic effusion and empyema [8]), whereas macrophage inflammatory protein (MIP)-1 and monocyte chemoattractant protein (MCP)-1 are increased in monocyte-rich tuberculous effusions (8, 9). In this issue of the AJRCMB , Katayama and coworkers report that normal human PMC secrete two potent eosinophilactive chemokines, namely, eotaxin and RANTES (10). Originally identified in BAL fluids in an animal model of allergic inflammation (11), eotaxin is now known to comprise a family of peptides that recognize the specific ligand chemokine receptor-3 (CCR3). The restricted expression of CCR3 to eosinophils, basophils, and mast cells helps explain the cell-type specific effects of eotaxin. RANTES binds in a more promiscuous fashion to CCR1-, CCR3-, and CCR5expressing cells, and thus it is chemotactic for eosinophils as well as monocytes and lymphocytes in vivo (12). Several features of the study by Katayama and colleagues are noteworthy (10). First, the authors studied primary human mesothelial cells obtained from the cellular fraction of pleural effusions and expanded by epidermal growth factor (EGF) for several weeks. Prior work by this group demonstrated that mesothelial cells obtained in this fashion were phenotypically identical to normal PMC, including staining positive for keratin and vimentin, and expressing surface microvilli (13). Second, the expression of eotaxin and RANTES by PMC was found to be enhanced by Th2 (IL-4) and Th1 (IFN) cytokines, respectively, both of which acted in synergy with TNF. This is in keeping with a recent study showing that mouse PMC express surface receptors for IL-4 and IFN(14). Third, the authors dissected the molecular mechanisms of cytokine-dependent eotaxin and RANTES expression in PMC, and report that this involves both transcriptional and post-transcriptional gene regulation. Work in other lung cell types, including airway epithelial cells (15, 16), smooth muscle cells (17), and fibroblasts (18), has uncovered distinct patterns of chemokine secretion in response to Th1 and Th2 cytokines. In general, the Th2 cytokines IL-4 and IL-13 are potent inducers of eotaxin secretion, whereas IFN(the prototypical Th1 cytokine) is a stronger inducer of RANTES expression. The effects of Th1 and Th2 cytokines on RANTES and eotaxin expression in these cells tend to be mutually antagonistic, and to synergize with the proinflammatory cytokine TNF. Human PMC fit nicely into this paradigm (10). Taken together with similar findings in endothelial cells (19), these studies demonstrate that multiple cell lineages of distinct embryologic origin secrete eotaxin in a Th2-dependent manner. This helps explain the close association between ( Received in original form February 21, 2002 )