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Generation of Th1 and Th2 Chemokines by Human Eosinophils: Evidence for a Critical Role of TNF-¹

Lin Ying Liu^*, Mary Ellen Bates, Nizar N. Jarjour^*, William W. Busse^*, Paul J. Bertics and Elizabeth A. B. Kelly^2,*

^* Section of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, and Department of Biomolecular Chemistry, University of Wisconsin School of Medicine, Madison, WI 53792

Emerging evidence suggests a role for eosinophils in immune regulation of T cells. Thus, we sought to determine whether human eosinophils may exert their effect via differential generation of Th1 and Th2 chemokines depending on cytokines in their microenvironment and, if so, to establish the conditions under which these chemokines are produced. Eosinophils cultured with TNF- plus IL-4 had increased mRNA expression and protein secretion of the Th2-type chemokines, CCL17 (thymus and activation-regulated chemokine) and CCL22 (macrophage-derived chemokine). Conversely, the Th1-type chemokines, CXCL9 (monokine induced by IFN-) and CXCL10 (IFN--inducible protein-10), were expressed after stimulation with TNF- plus IFN-. Addition of TNF- appeared to be essential for IFN--induced release of Th1-type chemokines and significantly enhanced IL-4-induced Th2-type chemokines. Inhibition of NF-B completely blocked the production of both Th1 and Th2 chemokines. Activation of NF-B, STAT6, and STAT1 was induced in eosinophils by TNF-, IL-4, and IFN-, respectively. However, there was no evidence for enhancement of these signaling events when eosinophils were stimulated with the combination of TNF- plus IL-4 or TNF- plus IFN-. Thus, independently activated signaling cascades appear to lead to activation of NF-B, STAT1, and STAT6, which may then cooperate at the promoter level to increase gene transcription. Our data demonstrate that TNF- is a vital component for eosinophil chemokine generation and that, depending on the cytokines present in their microenvironment, eosinophils can promote either a Th2 or a Th1 immune response, supporting an immunoregulatory role for eosinophils.

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 This work was supported in part by an institutional Specialized Center of Research grant (NIH HL56396) and a University of Wisconsin General Clinical Research Center grant (NIH M01RR03186).

² Address correspondence and reprint requests to Dr. Elizabeth A. B. Kelly, Section of Allergy, Pulmonary, and Critical Care Medicine, 600 Highland Avenue, CSC K4/928, University of Wisconsin School of Medicine, Madison, WI 53792-9988. E-mail address: eak{at}medicine.wisc.edu

³ Abbreviations used in this paper: GUS, -glucuronidase; Ct, cycle threshold.

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