title: Sigma receptor 1 activation attenuates release of inflammatory cytokines MIP1γ, MIP2, MIP3α, and IL12 (p40/p70) by retinal Müller glial cells.
abstract: The high-affinity sigma receptor 1 (σR1) ligand (+)-pentazocine ((+)-PTZ) affords profound retinal neuroprotection in vitro and in vivo by a yet-unknown mechanism. A common feature of retinal disease is Müller cell reactive gliosis, which includes cytokine release. Here, we investigated whether lipopolysaccharide (LPS) stimulates cytokine release by primary mouse Müller cells and whether (+)-PTZ alters release. Using a highly sensitive inflammatory antibody array we observed significant release of macrophage inflammatory proteins (MIP1γ, MIP2, MIP3α) and interleukin-12 (IL12 (p40/p70)) in LPS-treated cells compared to controls, and a significant decrease in secretion upon (+)-PTZ treatment. Müller cells from σR1 knockout mice demonstrated increased MIP1γ, MIP2, MIP3α and IL12 (p40/p70) secretion when exposed to LPS compared to LPS-stimulated WT cells. We investigated whether cytokine secretion was accompanied by cytosolic-to-nuclear NFκB translocation and whether endothelial cell adhesion/migration was altered by released cytokines. Cells exposed to LPS demonstrated increased NFκB nuclear location, which was reduced significantly in (+)-PTZ-treated cells. Media conditioned by LPS-stimulated-Müller cells induced leukocyte-endothelial cell adhesion and endothelial cell migration, which was attenuated by (+)-PTZ treatment. The findings suggest that release of certain inflammatory cytokines by Müller cells can be attenuated by σR1 ligands providing insights into the retinal neuroprotective role of this receptor.
authors.affiliation: Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA.|James and Jean Culver Vision Discovery Institute, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: Arul
authors.initials: A
authors.lastname: Shanmugam
authors.affiliation: Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA.|James and Jean Culver Vision Discovery Institute, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA.|James and Jean Culver Vision Discovery Institute, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: Shanu
authors.initials: S
authors.lastname: Markand
authors.affiliation: Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA.|James and Jean Culver Vision Discovery Institute, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Perry
authors.affiliation: Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA.|James and Jean Culver Vision Discovery Institute, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: Amany
authors.initials: A
authors.lastname: Tawfik
authors.affiliation: Harold L. Dorris Neurological Research Institute, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Zorrilla
authors.affiliation: James and Jean Culver Vision Discovery Institute, Georgia Regents University, Augusta, Georgia, USA.|Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: Vadivel
authors.initials: V
authors.lastname: Ganapathy
authors.affiliation: Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA.|James and Jean Culver Vision Discovery Institute, Georgia Regents University, Augusta, Georgia, USA.|Department of Ophthalmology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: Sylvia B
authors.initials: SB
authors.lastname: Smith
mesh_terms: D000818:Animals; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D063928:Ependymoglial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010423:Pentazocine / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D017480:Receptors, sigma / Q000276:immunology / Q000378:metabolism*; D000097605:Sigma-1 Receptor
chemical_list: D016207:Cytokines; D018696:Neuroprotective Agents; D010423:Pentazocine; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor
keywords: (+)-pentazocine; cytokine array; mouse; radial glial cell; retinal degeneration; retinal disease