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The Adaptor Protein p62 Mediates Nuclear Factor κB Activation in Response to Inflammation and Facilitates the Formation of Prolabor Mediators in Human Myometrium

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Abstract

Preventing spontaneous preterm birth is one of the most important issues facing perinatal medicine today. The pathophysiology of preterm labor, the single biggest cause of preterm birth, is poorly understood. Inflammation, however, plays a significant role in the terminal processes of human labor, which include myometrial contractions. Nuclear factor κB (NF-κB) drives the transcription of proinflammatory mediators involved in the terminal effector pathways of human labor and delivery. Recent studies in nongestational tissues have shown that the adaptor protein p62 interacts with NF-κB to induce inflammation. The aim of this study was to determine the role of p62 in the genesis of NF-κB-induced proinflammatory and prolabur mediators. Human spontaneous term labor was associated with increased p62 messenger RNA (mRNA) and protein expression in myometrium. Myometrial cells treated with proinflammatory cytokines interleukin Iβ (IL-Iβ) and tumor necrosis factor alpha (TNF-α) also significantly increased p62 mRNA and protein expression. Functional studies using p62 small interfering RNA (siRNA) demonstrated a significant attenuation of TNF-α- and IL-Iβ-induced proinflammatory cytokines (IL-6) and chemokine (IL-8 and monocyte chemoattractant protein I [MCP-I]) mRNA expression and secretion, expression of cyclooxygenase 2, release of prostaglandin F2α (PGF2α), and expression of the prostaglandin F receptor (FP). In addition, siRNA knockdown of p62 significantly suppressed IL-Iβ- and TNF-α-induced NF-κB activation. Collectively, these studies suggest that p62 is involved in the genesis of NF-κB-induced proinflammatory and prolabor mediators.

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Authors and Affiliations

  1. Department of Obstetrics and Gynaecology, University of Melbourne, Obstetrics, Nutrition and Endocrinology Group, Mercy Hospital for Women, Level 4/163 Studley Road, Heidelberg, 3084, Victoria, Australia

    Martha Lappas PhD

  2. Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia

    Martha Lappas PhD

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  1. Martha Lappas PhD
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Correspondence to Martha Lappas PhD.

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Lappas, M. The Adaptor Protein p62 Mediates Nuclear Factor κB Activation in Response to Inflammation and Facilitates the Formation of Prolabor Mediators in Human Myometrium. Reprod. Sci. 24, 762–772 (2017). https://doi.org/10.1177/1933719116669058

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