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 PD 98059 and SB 203580 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-κB), 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.
| Original language | English |
|---|---|
| Pages (from-to) | 242-249 |
| Number of pages | 8 |
| Journal | Cytokine |
| Volume | 19 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2002 |
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Keywords
- Human monocytes/IL-8/MCP-1/M
- Tuberculosis/signalling pathways
ASJC Scopus subject areas
- Endocrinology
- Molecular Biology
- Immunology
- Immunology and Allergy
Cite this
Pharmacological analysis of signal transduction pathways required for mycobacterium tuberculosis-induced iL-8 and MCP-1 production in human peripheral monocytes. / Fietta, Anna M.; Morosini, Monica; Meloni, Federica; Bianco, Alessia Marone; Pozzi, Ernesto.
In: Cytokine, Vol. 19, No. 5, 2002, p. 242-249.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Pharmacological analysis of signal transduction pathways required for mycobacterium tuberculosis-induced iL-8 and MCP-1 production in human peripheral monocytes
AU - Fietta, Anna M.
AU - Morosini, Monica
AU - Meloni, Federica
AU - Bianco, Alessia Marone
AU - Pozzi, Ernesto
PY - 2002
Y1 - 2002
N2 - 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 PD 98059 and SB 203580 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-κB), 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.
AB - 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 PD 98059 and SB 203580 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-κB), 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.
KW - Human monocytes/IL-8/MCP-1/M
KW - Tuberculosis/signalling pathways
UR - http://www.scopus.com/inward/record.url?scp=0036036011&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036036011&partnerID=8YFLogxK
U2 - 10.1016/S1043-4666(02)91968-X
DO - 10.1016/S1043-4666(02)91968-X
M3 - Article
C2 - 12393171
AN - SCOPUS:0036036011
VL - 19
SP - 242
EP - 249
JO - Cytokine
JF - Cytokine
SN - 1043-4666
IS - 5
ER -