Inflammatory Responses. Inlammatory responses drive the pathogenesis of infection-induced preterm labor. lipopolysaccharide (LPS) or other toxins elaborated by bacteria are recognized by pattern-recognition receptors such as toll-like receptors (Janssens, 2003). hese receptors are present on mononuclear phagocytes, decidual cells, cervical epithelia, and trophoblasts (Chuang, 2000; Gonzalez, 2007; Holmlund, 2002). Loss of specific toll-like receptors results in delayed parturition in mouse models (Montalbano, 2013). Instead, activation of tolllike receptors induces a signaling cascade that activates production of chemokines such as interleukin 8 (IL-8) and cytokines such as IL-13. Activation also recruits immune cells into the reproductive tract. Cytokines are produced by immune cells and by cells within the cervix, decidua, membranes, or fetus itsel.
LPS-induced production ofIL-13 in turn promotes a series of responses that include: (1) increased synthesis of others, that is, IL-6, IL-8, and tumor-necrosis factor alpha (TNF-.); (2) proliferation, activation, and migration of leukocytes; (3) modiications in extracellular matrix proteins; and (4) mitogenic and cytotoxic efects such as fever and acute-phase response (EI-Bastawissi, 2000). Also, in many tissues, including myometrium, decidua, and amnion, IL-1 3 promotes prostaglandin formation that induces cervical ripening and loss of myometrial quiescence (Casey, 1990; Challis, 2002; Keelan, 2003). he importance of prostaglandins to infection-mediated pre term birth is supported by the observation that prostaglandin inhibi tors can reduce the rate of LPS-induced preterm birth in both the mouse and nonhuman primate (Gravett, 2007; Timmons, 2014). Inhibition of cyclooxygenase-2 prevents inlammation mediated preterm labor in the mouse. And, immunomodula intraamnionic infection in a nonhuman primate model.
Proteases such as matrix metalloproteinases (MMPs) are also induced by IL-1 3 and function to break down extracel lular matrix components such as collagen or elastic ibers. This disrupts the structural integrity of fetal membranes and the cer vix. Current evidence from animal and human studies suggests that many aspects of infection-mediated preterm birth difer from pathways that regulate term parturition (Hamilton, 2012; Holt, 2011; Shynlova, 2013a,b; Timmons, 2014).
Origin of Cytokines. Uterine cytokines are likely important for preterm labor. For example, it appears that cytokines produced side, whereas cytokines produced in the membranes or in cells within the amnionic fluid will not be transferred to maternal tissues. he transfer of cytokines such as IL-1 3 from decidua across the membranes into amnionic luid, however, appears to be severely limited. Additionally, the human myometrium expresses chemokine receptors that decline during labor (Hua, 2013).