Interleukin 10 modulation of tumour necrosis factor receptors requires tyrosine kinases but not the PI 3-kinase/p70 S6 kinase pathway.
We have previously shown that interleukin (IL-)10-induced proliferation of the murine mast cell line D36, was dependent upon the activation of PI 3-kinase and p70 S6 kinase. Conversely, we were able to show that this pathway was not involved in the signal transduction pathway mediating IL-10 inhibition of pro-inflammatory cytokine release from monocytes. We have extended these studies to investigate the induction of p75 tumour necrosis factor receptor (TNF-R) shedding, another anti-inflammatory property of IL-10. Using the inhibitors of PI 3-kinase (LY294002 and wortmannin) and an inhibitor of p70 S6 kinase activation (rapamycin), we were able to show that this anti-inflammatory effect of IL-10 was not mediated by the PI 3-kinase/p70 S6 kinase pathway, indicating that another signalling cascade(s) was involved. Further studies also investigated the role of tyrosine kinases in the response to IL-10. Two distinct tyrosine kinase inhibitors, herbimycin and genistein affected the expression of TNF-R in response to IL-10 but, surprisingly, with opposite effects. However, both compounds inhibited the activation of both PI 3-kinase and p70 S6 kinase, with a concomitant inhibition of IL-10-induced proliferation. We observed that whilst tyrosine kinase activity was involved in the regulation of TNF-R expression, IL-10-induced activation of JAK kinases was not sensitive to inhibition by the tyrosine kinase inhibitors. These data suggest that multiple unknown tyrosine kinases are mediating the IL-10-induced signal transduction pathways leading to the regulation of TNF-R expression and IL-10-induced proliferation.
Williams
L
L
Kennedy Institute of Rheumatology, London, W6 8LH, UK.
Lali
F
F
Clarke
C
C
Brennan
F
F
Foxwell
B
B
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D016227:Benzoquinones; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D016753:Interleukin-10 / Q000378:metabolism*; D053613:Janus Kinase 1; D047029:Lactams, Macrocyclic; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011809:Quinones / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction; D020032:Tyrphostins / Q000494:pharmacology
D015703:Antigens, CD; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D019833:Genistein; D016753:Interleukin-10; D053613:Janus Kinase 1; D047029:Lactams, Macrocyclic; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011809:Quinones; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D019893:Ribosomal Protein S6 Kinases; D017828:Rifabutin; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C020754:herbimycin; C507905:Jak1 protein, mouse