Fever, sickness behavior, and expression of inflammatory genes in the hypothalamus after systemic and localized subcutaneous stimulation of rats with the Toll-like receptor 7 agonist imiquimod

Neuroscience. 2012 Jan 10;201:166-83. doi: 10.1016/j.neuroscience.2011.11.013. Epub 2011 Nov 12.

Abstract

The Toll-like receptor 7 (TLR7) agonist imiquimod is used for topical treatment of skin cancers. We studied the consequences of injections of imiquimod into a subcutaneous (s.c.) air pouch or of intraperitoneal (i.p.) injections on the manifestation of fever, sickness behavior, and the peripheral and brain-intrinsic induction of a variety of inflammatory molecules. Rats were given imiqimod s.c. or i.p. (1 or 5 mg/kg). Body temperature, motor activity, and food and water intake were recorded by telemetric devices. Peripheral and brain-intrinsic induction of inflammatory mediators was analyzed by real-time polymerase chain reaction (RT-PCR), bioassays, enzyme-linked immunosorbent assays (ELISAs), and immunohistochemistry. Imiquimod is the first TLR-agonist to produce more potent effects with s.c. than i.p. administration. Peripheral induction of interferons (IFNs) and putative circulating pyrogens corresponded to the magnitude of the illness responses. In the brain, an expression of cytokines (TNFα, IL-1β, and IL-6) and inducible forms of enzymes for prostaglandin E2 synthesis (COX-2 and mPGES) occurred, which was accompanied by a moderate activation of the transcription factors NFκB and STAT3, and a strong activation of the transcription factor NF-IL6, in cells of specific areas with an open blood-brain barrier. These inflammatory responses noted within the brain were more marked after s.c. administration, than i.p. administration of imiquimod. At a dose of 5 mg/kg, imiquimod causes rather moderate brain-inflammatory responses, which are related to peripheral IFN-expression and possibly mediated by brain-intrinsic activation of NF-IL6 and induction of a proinflammatory cocktail. The lack of a septic-like state in imiquimod-treated rats reinforces the therapeutic use of this drug.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / adverse effects*
  • Aminoquinolines / adverse effects*
  • Analysis of Variance
  • Animals
  • Body Temperature / drug effects
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Cytokines / blood*
  • Cytokines / genetics
  • Dose-Response Relationship, Drug
  • Drinking / drug effects
  • Drug Administration Routes
  • Eating / drug effects
  • Enzyme-Linked Immunosorbent Assay
  • Fever / chemically induced*
  • Gene Expression Regulation / drug effects*
  • Hypothalamus / drug effects*
  • Illness Behavior / drug effects*
  • Imiquimod
  • Intramolecular Oxidoreductases / genetics
  • Intramolecular Oxidoreductases / metabolism
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Motor Activity / drug effects
  • Rats
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Spleen / drug effects
  • Spleen / metabolism
  • Time Factors
  • Wisteria

Substances

  • Adjuvants, Immunologic
  • Aminoquinolines
  • Cytokines
  • STAT3 Transcription Factor
  • Cyclooxygenase 2
  • Intramolecular Oxidoreductases
  • membrane-associated PGE synthase, rat
  • Imiquimod