Stress and substance P but not the substance P-metabolite SP5-11 trigger murine abortion by augmenting TNF-alpha levels at the feto-maternal interface.
In a well-established murine abortion model, stress is thought to trigger fetal rejection by inducing a proinflammatory immune response via substance P (SP), being tumour necrosis factor (TNF)-alpha-producing CD8+ T cells involved. Interestingly, the SP metabolite SP5-11 also binds to SP receptors and mediates SP-like effects on immune cells at sites of inflammation. No data were available regarding the effects of SP5-11 on pregnancy outcome in the CBA/J x DBA/2J abortion-prone combination. We investigated the influence of SP5-11 in contrast to stress or SP on the abortion rate and the cytokine production by lymphocytes as well as on the levels of CD8+ T cells. Stress and SP boosted the abortion rate and increased the percentage of type 1 [TNF-alpha, interferon-gamma, interleukin (IL)-12] and type 2 (IL-4 and IL-10) cytokine-producing lymphocytes in blood and decidua, predominantly CD8+ T cells. Interestingly, SP5-11 did not significantly affect the abortion rate or cytokine production in the decidua, while increasing the Th1 and Th2 cytokine production systemically. Our data suggest that stress and SP induce abortion by augmenting the local levels of TNF-alpha, which seems therefore to be a potent trigger of miscarriage. On the contrary, the SP metabolite SP5-11 only affects the systemic cytokine production without boosting the abortion rate in this experimental model.
Fest
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Department of General Pediatrics, Charité, Humboldt-University, Biomedizinisches Forschungszentrum, Berlin, Germany. stefan.fest@charite.de
Zenclussen
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AC
Joachim
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Hagen
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Demuth
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HU
Hoffmann
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D000022:Abortion, Spontaneous / Q000139:chemically induced / Q000209:etiology / Q000276:immunology*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D003656:Decidua / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D005260:Female; D018655:Lymphocyte Count; D008431:Maternal-Fetal Exchange / Q000276:immunology; D051379:Mice; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D010446:Peptide Fragments / Q000494:pharmacology* / Q000633:toxicity; D011247:Pregnancy; D013312:Stress, Physiological / Q000276:immunology*; D013373:Substance P / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D016207:Cytokines; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C508295:substance P-metabolite 5-11; D013373:Substance P