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Interleukin-4 deficiency induces mild preeclampsia in mice

Chatterjee, Piyalia; Kopriva, Shelley E.a; Chiasson, Valorie L.a; Young, Kristina J.a,b; Tobin, Richard P.b; Newell-Rogers, Karenb; Mitchell, Brett M.a

doi: 10.1097/HJH.0b013e328360ae6c
ORIGINAL PAPERS: Inflammation

Objective: Inflammation is necessary for successful pregnancy; however, excessive inflammation plays a central role in the development of the pregnancy-specific hypertensive disorder preeclampsia. Numerous anti-inflammatory cytokines are decreased in women with preeclampsia but the role of individual cytokines in blood pressure regulation during pregnancy is unknown. Therefore, we examined whether the lack of the potent anti-inflammatory cytokine interleukin-4 (IL-4) would be sufficient to elicit a preeclampsia-like syndrome in mice, and when coupled with immune system activation that these symptoms would be further augmented.

Methods: Measures of splenic immune cells, placental inflammation, blood pressure, endothelial function, and urinary protein excretion were performed in pregnant IL-4-deficient mice as well as in pregnant IL-4-deficient mice treated with the Toll-like receptor 3 agonist polyinosinic:polycytidylic (poly I:C).

Results: Pregnant IL-4-deficient mice exhibited altered splenic immune cell subsets, increased levels of pro-inflammatory cytokines, placental inflammation, mild hypertension, endothelial dysfunction, and proteinuria compared to pregnant control mice. Compared to pregnant control mice treated with poly I:C which exhibit preeclampsia-like symptoms, poly I:C-treated pregnant IL-4-deficient mice exhibited a further increase in pro-inflammatory cytokine levels, which was associated with augmented SBP and endothelial dysfunction.

Conclusion: Collectively, these data show that the absence of IL-4 is sufficient to induce mild preeclampsia-like symptoms in mice due to excessive inflammation. Thus, the anti-inflammatory effects of IL-4 are important in preventing hypertension during pregnancy.

aDepartment of Internal Medicine

bDepartment of Surgery, Texas A&M Health Science Center/Scott & White Memorial Hospital, Temple, Texas, USA

Correspondence to Brett M. Mitchell, PhD, Department of Internal Medicine, Texas A&M Health Science Center/Scott & White Memorial Hospital, 702 SW HK Dodgen Loop, Temple, TX 76504, USA. Tel: +1 254 724 6267; fax: +1 254 724 7093; e-mail: bmitchell@tamhsc.edu

Abbreviations: ACh, acetylcholine; DAMPs, danger-associated molecular patterns; ICAM-1, intracellular adhesion molecule-1; IFNγ, interferon γ; IL, interleukin; PAMPs, pathogen-associated molecular patterns; poly I???C, polyinosinic???polycytidylic; SNP, sodium nitroprusside; TGFβ1, transforming growth factor β1; Th, T helper type; TLR, Toll-like receptor; TNFα, tumor necrosis factor α

Received 9 November, 2012

Revised 8 February, 2013

Accepted 27 February, 2013

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© 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins