Suppression of p21Rac signaling and increased innate immunity mediate remission in Crohn's disease.
In inflammatory bowel disease (IBD), large areas of apparently healthy mucosa lie adjacent to ulcerated intestine. Knowledge of the mechanisms that maintain remission in an otherwise inflamed intestine could provide important clues to the pathogenesis of this disease and provide rationale for clinical treatment strategies. We used kinome profiling to generate comprehensive descriptions of signal transduction pathways in inflamed and noninflamed colonic mucosa in a cohort of IBD patients, and compared the results to non-IBD controls. We observed that p21Rac1 guanosine triphosphatase (GTPase) signaling was strongly suppressed in noninflamed colonic mucosa in IBD. This suppression was due to both reduced guanine nucleotide exchange factor activity and increased intrinsic GTPase activity. Pharmacological p21Rac1 inhibition correlated with clinical improvement in IBD, and mechanistically unrelated pharmacological p21Rac1 inhibitors increased innate immune functions such as phagocytosis, bacterial killing, and interleukin-8 production in healthy controls and patients. Thus, suppression of p21Rac activity assists innate immunity in bactericidal activity and may induce remission in IBD.
Department of Cell Biology, University Medical Center Groningen, University of Groningen, Deusinglaan 1, NL-9713 AV Groningen, the Netherlands.
Kaushal
K
Parikh
Lu
L
Zhou
Rajesh
R
Somasundaram
Gwenny M
GM
Fuhler
J Jasper
JJ
Deuring
Tjasso
T
Blokzijl
Anouk
A
Regeling
Ernst J
EJ
Kuipers
Rinse K
RK
Weersma
Veerle J
VJ
Nuij
Maria
M
Alves
Lauran
L
Vogelaar
Lydia
L
Visser
Colin
C
de Haar
Kausilia K
KK
Krishnadath
C Janneke
CJ
van der Woude
Gerard
G
Dijkstra
Klaas Nico
KN
Faber
Maikel P
MP
Peppelenbosch
D000818:Animals; D001706:Biopsy; D003424:Crohn Disease / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020690:GTPase-Activating Proteins / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007113:Immunity, Innate; D007249:Inflammation / Q000473:pathology; D007413:Intestinal Mucosa / Q000473:pathology; D011494:Protein Kinases / Q000378:metabolism; D012074:Remission Induction; D015398:Signal Transduction; D013866:Thioguanine / Q000494:pharmacology; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D011494:Protein Kinases; D020830:rac1 GTP-Binding Protein; D013866:Thioguanine