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Cytokine–Chemokine Networks in Experimental Mycobacterial and Schistosomal Pulmonary Granuloma Formation

Department of Pathology, University of Michigan Medical School; and the Department of Pathology and Laboratory Medicine, Veterans Affairs Healthcare System, Ann Arbor, Michigan

Address correspondence to: Stephen W. Chensue, M.D., Ph.D., Pathology and Laboratory Medicine 113, Veterans Affairs Medical Center, 2215 Fuller Road, Ann Arbor, MI 48105. E-mail: schensue{at}med.umich.edu

Type-1 and type-2 lung granulomas, respectively, elicited by bead immobilized Mycobacteria bovis and Schistosoma mansoni egg antigens (Ags) display different patterns of chemokine expression. This study tested the hypothesis that chemokine expression patterns were related to upstream cytokine signaling. Using quantitative transcript analysis, we defined expression profiles for 16 chemokines and then examined the in vivo effects of neutralizing antibodies against interferon- (IFN-), interleukin (IL)-4, IL-10, IL-12, and IL-13. Transcripts for CXCL2, -5, -9, -10, and -11 and the CCL chemokine, CCL3, and lymphotactin (XCL1), were largely enhanced by Th1-related cytokines, IFN- or IL-12. Transcripts for CCL11, CCL22, CCL17, and CCL1 were enhanced largely by Th2-related cytokines, IL-4, IL-10, or IL-13. Transcripts for CCL4, CCL2, CCL8, CCL7, and CCL12 were potentially induced by either Th1- or Th2-related cytokines, although some of these showed biased expression. IFN- and IL-4 enhanced the greatest complement of transcripts, and their neutralization had the greatest anti-inflammatory effect on type-1 and type-2 granulomas, respectively. Th1/Th2 cross-regulation was evident because endogenous Th2 cytokines inhibited type-1, whereas Th1 cytokines inhibited type-2 biased chemokines. These findings reveal a complex cytokine–chemokine regulatory network that dictates profiles of local chemokine expression during T cell–mediated granuloma formation.

Abbreviations: antigens, Ags • CC chemokine ligand, CCL • complete Freund's adjuvant, CFA • CXC chemokine ligand, CXCL • enzyme-linked immunosorbent assay, ELISA • interferon-, IFN- • interleukin, IL • monocyte chemotactic protein, MCP • macrophage inflammatory protein, MIP • phosphate-buffered saline, PBS • purified protein derivative of mycobacteria, PPD • schistosomal soluble egg antigen, SEA • tumor necrosis factor, TNF

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