The role of IFN-gamma in regulation of IFN-gamma-inducible protein 10 (IP-10) expression in lung epithelial cell and peripheral blood mononuclear cell co-cultures.
BACKGROUND
Interferons play a critical role in regulating both the innate and adaptive immune responses. Previous reports have shown increased levels of IFN-gamma, IFN-gamma-inducing IL-12 and IFN-gamma-inducible chemokine IP-10 in patients with chronic obstructive pulmonary disease (COPD).


METHODS
The present study focuses on the regulation of the IP-10 secretion in co-cultures of lung epithelial cells and peripheral blood mononuclear cells (PBMCs).


RESULTS
No IP-10 secretion was detected in cells cultured alone, whereas a significant increase in IP-10 levels was observed in epithelial cell/PBMC co-cultures. Furthermore, the results show that interactions between lung epithelial cells, lymphocytes and monocytes are needed for basal IP-10 secretion. Interestingly, we have also shown that incubation with IL-12 can induce an IFN-gamma independent increase in IP-10 levels in co-cultures. Furthermore, inhibition studies supported the suggestion that different intracellular pathways are responsible of IFN-gamma and IL-12 mediated IP-10 secretion.


CONCLUSIONS
These studies demonstrate a novel diversity in IFN-gamma/IL-12 pathways, showing that the IP-10 expression in co-cultures is regulated by multiple factors, such as intercellular interactions in addition to IFN-gamma and IL-12 levels. These results may be valuable in designing novel strategies to antagonize IP-10 mediated immunological reactions and chemotactic effects on T cells.
Torvinen
Maria
M
Pfizer Global R&D, Dep, Allergy and Respiratory, 500, Pfizer Ltd,, Sandwich, Kent, CT13 9NJ, UK. torvinenm@corning.com
Campwala
Hinnah
H
Kilty
Iain
I
D000906:Antibodies; D001507:Beclomethasone / Q000494:pharmacology; D045744:Cell Line, Tumor; D054357:Chemokine CXCL10 / Q000378:metabolism*; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009281:Naphthalenes / Q000494:pharmacology; D019899:Paracrine Communication / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D020889:Rolipram / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010671:Phenylurea Compounds
D000906:Antibodies; D001507:Beclomethasone; D054357:Chemokine CXCL10; D017077:Culture Media, Conditioned; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D051550:I-kappa B Kinase; D007371:Interferon-gamma; D018664:Interleukin-12; D009281:Naphthalenes; D019869:Phosphatidylinositol 3-Kinases; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011994:Recombinant Proteins; D020889:Rolipram; D048051:p38 Mitogen-Activated Protein Kinases; C114753:CXCL10 protein, human; C452139:doramapimod; D010671:Phenylurea Compounds