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* Division of Dermatology, Department of Medicine, and Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and
Institute for Medical Microbiology and Hygiene, University of Ulm, Ulm, Germany
Host defense against intracellular pathogens depends upon innate and adaptive antimicrobial effector pathways. TLR2/1-activation of monocytes leads to the vitamin D-dependent production of cathelicidin and, at the same time, an antimicrobial activity against intracellular Mycobacterium tuberculosis. To determine whether induction of cathelicidin was required for the vitamin D-triggered antimicrobial activity, the human monocytic cell line THP-1 was infected with M. tuberculosis H37Ra and then activated with the active vitamin D hormone 1,25-dihydroxyvitamin D3 (1,25D3). 1,25D3 stimulation resulted in antimicrobial activity against intracellular M. tuberculosis and expression of cathelicidin mRNA and protein. Using small interfering RNA (siRNA) specific for cathelicidin, 1,25D3-induced cathelicidin mRNA and protein expressions were efficiently knocked down, whereas a nonspecific siRNA control had little effect. Finally, 1,25D3-induced antimicrobial activity was completely inhibited in the presence of siRNA against cathelicidin, instead leading to enhanced intracellular growth of mycobacteria. These data demonstrate that cathelicidin is required for the 1,25D3-triggered antimicrobial activity against intracellular M. tuberculosis.
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 National Institutes of Health Grants R01 AI22553, R01 AI47868, and R01 AR40312. P.T.L. is supported by Microbial Pathogenesis Training Grant 2-T32-AI-07323. S.S. is funded by Deutsche Forschungsgemeinschaft SFB 643.
2 Address correspondence and reprint requests to Dr. Robert L. Modlin, Division of Dermatology, University of California Los Angeles, 52-121 Center for the Health Sciences, 10833 Le Conte Avenue, Los Angeles, CA 90095. E-mail address: rmodlin{at}mednet.ucla.edu
3 Abbreviations used in this paper: 1,25D3, 1,25-dihydroxyvitamin D3; MOI, multiplicity of infection; qPCR, quantitative PCR; siRNA, small interfering RNA; siCath, siRNA specific for the cathelicidin gene; ciCTRL, nonspecific siRNA control oligo.
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