Down regulation of cytokine secretion by MAPK inhibitors in IBD

DOCENA G; FANNING A; ROVEDATTI L; LEAKEY N; KNOWLES C; LEE K; SHANAHAN L; NALLY K; MCLEAN P; MACDONALD T; KRUIDENIER L

MILAN, ITALIA

Congreso; 6th European Mucosal Immunology Group Meeting; 2008

<!-- /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin:0cm; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman"; mso-ansi-language:EN-US; mso-fareast-language:EN-US;} @page Section1 {size:21.0cm 842.0pt; margin:72.0pt 89.85pt 72.0pt 89.85pt; mso-header-margin:35.45pt; mso-footer-margin:35.45pt; mso-paper-source:0;} div.Section1 {page:Section1;} --> Pro-inflammatory cytokines are key pathophysiologic factors in IBD, but the regulatory role of MAPK pathways in their expression has remained controversial.We have evaluated the activation status of p38 and JNK MAPK pathways and the inhibitory effect of novel p38 inhibitors. Fresh colonic biopsies and LPMC from normal subjects and patients with CD or UC were incubated in the presence or absence of four different p38 MAPK inhibitors (0.01–10uM). The activation status of p38α and JNK was evaluated by Western blotting, while levels of a range of cytokines were measured by multiplex ELISA. As compared to healthy controls, p38α and JNK phosphorylation levels, as well as TNF-α (30–500 pg/mL), IL-6 (1–30 ng/mL), IL-1β (20–1200 pg/mL) and monocyte chemoattractant protein (MCP)-1 (300–2000 pg/mL) were increased in CD and UC biopsies. Treatment with the different inhibitory drugs down modulated the phosphorylation of p38α and JNK MAPK, and the cytokine levels, in a dose-dependent manner.We confirm the importance of the p38 and JNK MAPK pathways in IBD, and identify novel p38 MAPK inhibitors which may constitute the basis for new therapeutic strategies in IBD patients.