Signals involved in mycobacteria-induced CXCL-8 production by human monocytes.
CXC chemokine-interleukin-8 (IL-8) (CXCL-8) is a potent proinflammatory chemotactic factor that induces important immune responses for antimycobacterial defenses. However, little is known about the biochemical mechanisms by which the mycobacterial antigens upregulate the release of CXCL-8 from human monocytes. In this study, the mechanisms through which Mycobacterium bovis BCG induces CXCL-8 secretion in human monocytes were investigated. We found that M. bovis BCG induced the production of high levels of CXCL-8 by human monocytes. M. bovis-induced CXCL-8 secretion was unaffected by the protein kinase C (PKC) inhibitor bisindolylmaleimide. In contrast, preincubation of the monocytes with the protein tyrosine kinase (PTK) inhibitor genistein resulted in dose-dependent suppression of mycobacteria-induced CXCL-8 secretion. These results were further supported by the fact that treatment of monocytes with herbimycin-A, another well-described inhibitor of PTK activity with a different mechanism of action, significantly diminished the effect of M. bovis on CXCL-8 secretion. In addition, the specificity of this inhibition was demonstrated by the inability of herbimycin-A to block in a significant manner IL-1 beta induction of CXCL-8. Herbimycin-A significantly blocked tyrosine phosphorylation of p59(hck) in response to M. bovis. Finally, two specific NF-kappa B inhibitors, sulfasalazine and caffeic acid phenetyl ester (CAPE), strongly inhibited the production of CXCL-8 by human monocytes infected with M. bovis. These results show intracellular signaling pathways and a transcription factor involved in the M. bovis-mediated upregulation of CXCL-8 biosynthesis and release by human monocytes.
Méndez-Samperio
P
P
Departamento de Immunologia, Escuela Nacional de Ciencias Biológicas, IPN, Carpio y Plan de Ayala, México, D.F. 11340 México. pmendezs@bios.encb.ipn.mx
Palma
J
J
Vázquez
A
A
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis*; D009000:Monocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D009163:Mycobacterium bovis / Q000254:growth & development / Q000276:immunology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D012460:Sulfasalazine / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D016209:Interleukin-8; D016328:NF-kappa B; D012460:Sulfasalazine; D019833:Genistein; D011505:Protein-Tyrosine Kinases