Differential lipopolysaccharide-induced immune alterations in the hippocampus of two mouse strains: effects of stress.
Immunological activation may result in the development of depressive-like symptoms in a large percentage of patients treated with cytokine-based therapies. The mechanisms underlying susceptibility to cytokine-induced depression are currently unknown; however activation of the tryptophan catabolising enzyme indoleamine 2,3-dioxygenase (IDO) is associated with the induction of cytokine-induced depression. Peripheral administration of lipopolysaccharide (LPS) is one of the most commonly used immunological challenges in animal models of cytokine-induced depression. Inbred mouse strains are useful tools in the investigation of the neurobiology of psychiatric illnesses. In this study we hypothesised that two strains which differ in stress susceptibility, namely the BALB/c and C57BL/6J mice, would respond differentially to LPS and swim-stress in cytokine profile, corticosterone concentrations and mRNA expression of genes coding for the tryptophan metabolising enzymes, IDO1, IDO2, Tph1 and Tph2. The stress-sensitive BALB/c strain exhibited increased depressive-like behaviour and enhanced corticosterone concentrations in response to LPS. Furthermore, swim-stress attenuated the LPS-induced corticosterone response in BALB/c mice only. LPS significantly increased plasma interleukin (IL)-1β and tumour necrosis factor α (TNFα) concentrations to a greater extent in BALB/c mice. The LPS-induced increase in IL-1β mRNA expression was significantly attenuated by swim-stress in the hippocampus of C57BL/6J but not in BALB/c mice. TNFα mRNA expression was significantly increased in BALB/c mice only; this increase was attenuated by swim-stress. Tph1 mRNA expression was upregulated in the brainstem of C57BL/6J mice post-LPS and following the combination of swim-stress and LPS in BALB/c mice. In the hippocampus Tph1 and Tph2 mRNA expression was increased in C57BL/6J but not BALB/c mice in response to LPS challenge and swim-stress. Conversely, IDO2 but not IDO1 mRNA expression was significantly altered following swim-stress and LPS, particularly in the hippocampus of BALB/c mice. These data indicate altered central mRNA expression of tryptophan metabolising enzymes and immune activation in BALB/c mice compared to the normo-sensitive C57BL/6J strain.
Neuropharmacology Research Group, Department of Pharmacology & Therapeutics, University College Cork, Cork, Ireland.
C A
CA
Browne
F E
FE
O'Brien
T J
TJ
Connor
T G
TG
Dinan
J F
JF
Cryan
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D003345:Corticosterone / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013045:Species Specificity; D013315:Stress, Psychological / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D013550:Swimming / Q000523:psychology; D013997:Time Factors; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008070:Lipopolysaccharides; C487801:Tph1 protein, mouse; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase; D003345:Corticosterone