Anti-inflammatory effects of the GABA(B) receptor agonist baclofen in allergic contact dermatitis.
The gamma amino butyric acid B (GABA(B)) receptor is a G protein-coupled receptor (GPCR) involved in synaptic transmission. Recent data indicate it to be also expressed on immune cells, along with chemokine receptors, which are also GPCRs. As GPCRs can undergo heterologous desensitization, we have examined the ability of baclofen, a GABA(B) receptor selective agonist, to interfere with the function of pro-inflammatory chemokine receptors known to be upregulated in cutaneous inflammation. In vitro, baclofen reduces chemotaxis of human peripheral blood mononuclear cells towards CCL2, CCL5, CXCL10, CXCL2 and CX3CL1 in a dose-dependant manner. Protein kinase C inhibitors calphostin C and G0 6976 could reverse this effect, pointing towards the involvement of both calcium-dependent and -independent protein kinase C in baclofen-induced inhibition of chemokine receptors. In an in vivo model of contact hypersensitivity in C57BL/6 mice, intraperitoneal injection of baclofen markedly alleviated signs of inflammation as well as recruitment of neutrophils, monocytes and lymphocytes into the skin. This study demonstrates a new role for the GABA(B) receptor in inflammation, making it a potential new therapeutic target to treat inflammatory skin diseases.
Duthey
Beatrice
B
Department of Dermatology, Clinic of the Johann Wolfgang Goethe-University, Theodor-Stern-Kai, Frankfurt, Germany.
Hübner
Anita
A
Diehl
Sandra
S
Boehncke
Sandra
S
Pfeffer
Jeannette
J
Boehncke
Wolf-Henning
WH
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001418:Baclofen / Q000494:pharmacology*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D017449:Dermatitis, Allergic Contact / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology; D058786:GABA-B Receptor Agonists; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D011493:Protein Kinase C / Q000378:metabolism; D020239:Receptor Cross-Talk; D019707:Receptors, Chemokine / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000893:Anti-Inflammatory Agents; D018755:GABA Agonists; D058786:GABA-B Receptor Agonists; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D011493:Protein Kinase C; D001418:Baclofen