title: Evidence for sustained elevation of IL-6 in the CNS as a key contributor of depressive-like phenotypes.
abstract: There is compelling clinical literature implicating a role for cytokines in the pathophysiology of major depressive disorder (MDD). Interleukin-6 (IL-6) and interleukin-1β (IL-1β) are pleiotropic inflammatory cytokines that have been reported to be elevated in patients with MDD. The present studies were undertaken to investigate the relationship between IL-6 and IL-1β in animal models of depressive-like behavior. Analysis of brain tissue homogenates in the cortex of rats subjected to chronic stress paradigms revealed elevated levels of IL-6 protein in the absence of elevations in IL-1β. Central administration of recombinant mouse IL-6 produced depressive-like phenotypes in mice, which were not accompanied by IL-1β-induced increases in the brain tissue or IL-1β-related sickness behavior typical of a general central nervous system inflammatory response. Systemic administration of fluoxetine in the presence of centrally administered IL-6 failed to produce the expected antidepressant-like response in mice relative to sham-infused controls. Further, administration of fluoxetine to mice with endogenous overexpression of brain IL-6 (MRL/MpJ-Fas(LPR/LPR) (LPR mice)) failed to produce the expected antidepressant-like effect relative to fluoxetine-treated control mice (MRL/MpJ(+/+)). Interestingly, blockade of IL-6 trans-signaling by coadministration of a gp130/Fc monomer or an anti-mouse IL-6 antibody with IL-6 prevented the IL-6-induced increases in immobility time as well as attenuated IL-6-induced increases of protein in the cortex. Taken together, these data indicate that elevations in IL-6 may have a pathophysiological role underlying depression and more specifically resistance to current classes of antidepressant medications and suggest that modulation of the IL-6 signaling pathway may have therapeutic potential for treatment-resistant depression.
authors.affiliation: Neuroscience Research Unit, Pfizer Research and Development, Cambridge, MA 02139, USA. Stacey.Rizzo@pfizer.com
authors.forename: S J
authors.initials: SJ
authors.lastname: Sukoff Rizzo
authors.forename: S J
authors.initials: SJ
authors.lastname: Neal
authors.forename: Z A
authors.initials: ZA
authors.lastname: Hughes
authors.forename: M
authors.initials: M
authors.lastname: Beyna
authors.forename: S
authors.initials: S
authors.lastname: Rosenzweig-Lipson
authors.forename: S J
authors.initials: SJ
authors.lastname: Moss
authors.forename: N J
authors.initials: NJ
authors.lastname: Brandon
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D050822:Cytokine Receptor gp130 / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy / Q000378:metabolism; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy / Q000378:metabolism*; D004195:Disease Models, Animal; D005473:Fluoxetine / Q000378:metabolism / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology; D015850:Interleukin-6 / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D005473:Fluoxetine; D050822:Cytokine Receptor gp130