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Diverse and Potent Chemokine Production by Lung CD11b^high Dendritic Cells in Homeostasis and in Allergic Lung Inflammation¹

Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, VA 22908

Lung CD11c^high dendritic cells (DC) are comprised of two major phenotypically distinct populations, the CD11b^high DC and the integrin _E7⁺ DC (CD103⁺ DC). To examine whether they are functionally distinguishable, global microarray studies and real-time PCR analysis were performed. Significant differences between the two major CD11c^high DC types in chemokine mRNA expression were found. CD11b^high DC is a major secretory cell type and highly expressed at least 16 chemokine mRNA in the homeostatic state, whereas CD103⁺ DC highly expressed only 6. Intracellular chemokine staining of CD11c^high lung cells including macrophages, and ELISA determination of sort-purified CD11c^high cell culture supernatants, further showed that CD11b^high DC produced the highest levels of 9 of 14 and 5 of 7 chemokines studied, respectively. Upon LPS stimulation in vitro and in vivo, CD11b^high DC remained the highest producer of 7 of 10 of the most highly produced chemokines. Induction of airway hyperreactivity and lung inflammation increased lung CD11b^high DC numbers markedly, and they produced comparable or higher amounts of 11 of 12 major chemokines when compared with macrophages. Although not a major producer, CD103⁺ DC produced the highest amounts of the Th2-stimulating chemokines CCL17/thymus and activation-related chemokine and CCL22/monocyte-derived chemokine in both homeostasis and inflammation. Significantly, CCL22/monocyte-derived chemokine exhibited regulatory effects on CD4⁺ T cell proliferation. Further functional analysis showed that both DC types induced comparable Th subset development. These studies showed that lung CD11b^high DC is one of the most important leukocyte types in chemokine production and it is readily distinguishable from CD103⁺ DC in this secretory function.

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 by U.S. Public Health Service Grants HL070065 and HL065344 from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Sun-sang J. Sung, Division of Rheumatology and Immunology, Department of Internal Medicine, Box 800412, University of Virginia Health Sciences Center, Charlottesville, VA 22908. E-mail address: sjs5c{at}Virginia.edu

³ Abbreviations used in this paper: AHR, airway hyperresponsiveness; 7-AAD, 7-aminoactinomycin D; BLC, B cell chemoattractant; CD103⁺ DC, integrin _E7⁺ DC; IP-10, IFN--inducible protein of 10 kDa; DC, dendritic cell; I-TAC, IFN--inducible T cell chemoattractant; MDC, monocyte-derived chemokine; MIG, monokine induced by IFN-; PDC, plasmacytoid DC; PF-4, platelet factor 4; PMN, neutrophil; poly(I:C), poly(deoxyinosinic-deoxycytidylic acid; TARC, thymus and activation-related chemokine; LPAM-1, lymphocyte Peyer’s patch high endothelial venule adhesion molecule 1.

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