Published ahead of print on January 10, 2003, doi:10.1165/rcmb.2002-0241OC
Am. J. Respir. Cell Mol. Biol., Volume 29, Number 1, July 2003, 106-116
A more recent version of this article appeared on July 1, 2003
Submitted on November 8, 2002
Revised on January 2, 2003
Cytokine-Chemokine Networks in Experimental Mycobacterial and Schistosomal Lung Granuloma Formation
Bo-Chin Chiu1, Christine M Freeman1, Valerie R Stolberg2, Eric Komuniecki1, Pamela M Lincoln1, Steven L Kunkel1, and Stephen W Chensue3*
1 Pathology, University of Michigan Medical School, Ann Arbor, MI, USA,
2 Pathology and Laboratory Medicine, VA Ann Arbor Healthcare System, Ann Arbor, MI, USA,
3 Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Pathology and Laboratory Medicine, VA Ann Arbor Healthcare System, Ann Arbor, MI, USA
* To whom correspondence should be addressed. E-mail: schensue{at}med.umich.edu.
Type-1 and type-2 lung granulomas respectively elicited by bead immobilized Mycobacteria bovis (PPD) and Schistosoma mansoni egg (SEA) Ags display different patterns 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-gamma (IFN ), interleukin-4 (IL-4), IL-10, IL-12, and IL-13. Transcripts for CXCL2, 5, 9, 10 and 11 and the CCL chemokines, 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 since 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.
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