title: Pharmacological analysis of signal transduction pathways required for mycobacterium tuberculosis-induced IL-8 and MCP-1 production in human peripheral monocytes.
abstract: Signalling cascades involved in chemokine production by human phagocytes following infection with Mycobacterium tuberculosis are still not defined. We used specific pharmacologic inhibitors to identify the signalling molecules which lead to interleukin (IL)-8 and MCP-1 production in human monocytes in response to M. tuberculosis infection. Inhibition of extracellular signal-regulated (ERK) or p38 mitogen-activated protein kinase by PD98059 and SB203580 respectively, significantly affected chemokine production. However, only the presence of both inhibitors completely blocked the release. A down-regulation of chemokine secretion was found in presence of inhibitors of protein kinase (PK)C and phospholipase C. Moreover, production depended on transcription activation via the nuclear factor-kappa B (NF-kappaB), as demonstrated by treatment with actinomycin D and caffeic acid phenethyl ester. In addition, activation of PKA and the phosphoinoside 3-kinase (PI-3k)/p70 ribosomal S6 kinase cascade was required to have maximal MCP-1 but not IL-8 production. In conclusion, this study provides evidence that multiple signal transduction pathways are involved in M. tuberculosis -induced chemokine secretion by human monocytes. Moreover, for the first time this report indicates that inhibitors of some signalling molecules are able to dissociate IL-8 from MCP-1 secretion. Differences in the regulatory pathways of chemokine production can potentially be exploited therapeutically.
authors.affiliation: Respiratory Disease Section, Department of Haematological, Pneumological and Cardiovascular Sciences, University of Pavia/IRCCS Policlinico San Matteo, Padiglione Forlanini, via Taramelli 5, 27100 Pavia, Italy. fiettanna@libero.it
authors.forename: Anna M
authors.initials: AM
authors.lastname: Fietta
authors.forename: Monica
authors.initials: M
authors.lastname: Morosini
authors.forename: Federica
authors.initials: F
authors.lastname: Meloni
authors.forename: Alessia Marone
authors.initials: AM
authors.lastname: Bianco
authors.forename: Ernesto
authors.initials: E
authors.lastname: Pozzi
mesh_terms: D018932:Chemokine CCL2 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology*; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism; D014376:Tuberculosis / Q000378:metabolism* / Q000382:microbiology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D016209:Interleukin-8; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D010738:Type C Phospholipases; D048051:p38 Mitogen-Activated Protein Kinases