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Monocyte-Dependent Fibroblast CXCL8 Secretion Occurs in Tuberculosis and Limits Survival of Mycobacteria within Macrophages¹

Cecilia M. O’Kane^*, Joseph J. Boyle, Donna E. Horncastle, Paul T. Elkington^* and Jon S. Friedland^2,*

^* Department of Infectious Diseases Immunity and Department of Histopathology, Imperial College, Hammersmith Campus, London, United Kingdom

CXCL8 is a chemokine that is implicated in the formation of tuberculous (TB) granulomas and in immunity to Mycobacterium tuberculosis (Mtb). Fibroblast chemokine secretion is important for modulating inflammatory responses in chronic lung disease and inflammatory arthritis but has not been investigated in the pathophysiology of TB. In this study, we used a cellular model to examine monocyte/macrophage-dependent stimulation of fibroblasts by Mtb in the regulation of chemokine secretion, particularly that of CXCL8. Human lung fibroblasts grown in collagen were stimulated with conditioned medium from Mtb-infected monocytes (CoMTb). CoMTb-induced prolonged dose-dependent, p38-mediated expression of stable CXCL8 mRNA by fibroblasts accompanied by a >10-fold increase in CXCL8 secretion (487 ± 88 ng/ml vs 48.6 ± 34 ng/ml in controls) at 120 h. Fibroblasts strongly expressed CXCL8 in vivo in human TB granulomas. Inhibition of TNF- or IL-1 in CoMTb abrogated the induction of CXCL8 at a pretranscriptional level. CXCL8 secretion was NF-B, C/EBP, and JNK dependent. Sustained NF-B activation was demonstrated beyond 24 h in response to CoMTb. Exogenous CXCL8 reduced the survival of Mtb within macrophages, and inhibition of CXCL8 was associated with intracellular mycobacterial proliferation. These data show that fibroblasts have a previously unrecognized role in modulating inflammation in TB by their CXCL8-dependent contribution to cell recruitment and mycobacterial killing within the granuloma.

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 funded by the Wellcome Trust (to C.M.O., P.T.E., and J.S.F.).

² Address correspondence and reprint requests to Prof. J. S. Friedland, Department of Infectious Diseases, Imperial College, Hammersmith Campus, Du Cane Road, London, U.K. E-mail address: j.friedland{at}imperial.ac.uk

³ Abbreviations used in this paper: TB, tuberculosis; Mtb, Mycobacterium tuberculosis; CoMcon, conditioned medium from uninfected monocytes; CoMTb, conditioned medium from Mtb-infected monocytes; MDM, monocyte-derived macrophage; MOI, multiplicity of infection; RPA, RNase protection assay.

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