Gene expression profiling reveals upregulation of Tlr4 receptors in Cckb receptor deficient mice.
The cholecystokinin B (2) receptor knockout (Cckbr KO) protects against allodynia induced by chronic constriction injury (CCI). The mechanism of this phenomenon is unknown, but must involve persistent changes in pain modulation and/or inflammatory pathways. We performed a gene expression study in two brain areas (midbrain and medulla) after surgical induction of CCI in Cckbr KO and wild-type (wt) control mice. The patterns of gene expression differences suggest that the immune system is activated in higher brain structures following CCI in the wt mice. The strongest differences include genes related to the MAPK pathway activation and cytokine production. In Cckbr KO mice this expressional pattern was absent. In addition, we found significant elevation of the Toll-like receptor 4 (Tlr4) in the supraspinal structures of the mice with deleted Cckbr compared to wt control mice. This up-regulation is most likely induced by the deletion of Cckbr. We suggest that there is a functional deficiency in the Tlr4 pathway which disables the development of neuropathic pain in Cckbr KO mice. Indeed, real time PCR analysis detected a CCI-induced upregulation of Tlr4 and Il1b expression in the lumbar region of wt but not Cckbr KO mice. Gene expression profiling indicates that elements of the immune response are not activated in Cckbr KO mice following CCI. Our findings suggest that there may be a role for CCK in the regulation of innate immunity.
Department of Physiology, Centre of Molecular and Clinical Medicine, University of Tartu, Tartu 50411, Estonia. Sulev.Koks@ut.ee <Sulev.Koks@ut.ee>
Sulev
S
Kõks
Cathy
C
Fernandes
Kaido
K
Kurrikoff
Eero
E
Vasar
Leonard C
LC
Schalkwyk
D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D008026:Ligation; D008159:Lumbar Vertebrae; D008297:Male; D008526:Medulla Oblongata / Q000276:immunology / Q000378:metabolism; D008636:Mesencephalon / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D017288:Pain Threshold / Q000502:physiology*; D043887:Receptor, Cholecystokinin B / Q000235:genetics / Q000502:physiology*; D020426:Sciatic Neuropathy / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D015854:Up-Regulation
D043887:Receptor, Cholecystokinin B; D051197:Toll-Like Receptor 4; D020929:Mitogen-Activated Protein Kinase Kinases