Systematic review of p38 mitogen-activated kinase and its functional role in reproductive tissues

Abstract

Oxidative stress (OS) plays a role in uterine tissue remodeling during pregnancy and parturition. While p38 MAPK is an OS-response kinase, a precise functional role is unknown. Therefore, we conducted a systematic review of literature on p38 MAPK expression, activation, and function in reproductive tissues throughout pregnancy and parturition, published between January 1980 and August 2017, using four electronic databases (Web of Science, PubMed, Medline, and CoCHRANE). We identified 418 reports; 108 were selected for full-text evaluation and 74 were included in final review. p38 MAPK was investigated using feto-maternal primary or immortalized cells, tissue explants, and animal models. Western blot was most commonly used to report phosphorylated (active) p38 MAPK. Human placenta (27), chorioamniotic membranes (14), myometrium (13), decidua (8), and cervix (1) were the studied tissues. p38 MAPK's functions were tissue and gestational age dependent. Isoform specificity was hardly reported. p38 MAPK activity was induced by ROS or proinflammatory cytokines to promote cell signaling linked to cell fate, primed uterus, ripened cervix, and proinflammatory cytokine/chemokine production. In 35 years, reports on p38 MAPK's role during pregnancy and parturition are scarce and current literature is insufficient to provide a comprehensive description of p38 MAPK's mechanistic role during pregnancy and parturition.

Keywords: MAPK signaling; amniochorion; cervix; decidua; myometrium; placenta.

Figure 1:

PRISMA Chart. Systematic review of article and selection for data extraction and analysis.

Figure 2:

Article count. Number of p38 MAPK articles published between 2000 and August 2017* *For 2017, we only analyzed articles published through August.

Figure 3:

Graphic summary of articles included in systematic review. Breakdown of p38 MAPK studies in species (inner circle), tissues (next to inner circle), cell types (outer circles), and number of articles (outer circle) identified in the systematic review.

Figure 4:

Main findings of p38 MAPK systematic review. A. The most studied tissue for p38 MAPK was the placenta, followed by the chorioamniotic membranes, myometrium, decidua, and cervix. B. The role of p38 MAPK in reproductive tissues has been studied predominantly in humans. C. Of the methods used, Western blot was the most commonly used technique to investigate total p38 MAPK and its phosphorylated (active) form. D. p38 MAPK has 4 different isoforms, and isoform expression is tissue specific. The majority of the studies in our review did not document the isoform studied. Among the reported ones, isoform α is the dominant isoform. Pharmaceutical inhibitors are also directed towards p38 MAPKα. E. The majority of inhibitors of p38 being tested and reported are pharmaceutical compounds (SB203580, SB202190). Small interfering RNAs were used in a few reports. Interestingly, some studies reported p38’s function without scientific rigor by having inhibitors in experimental models. F. The role of p38 MAPK has been studied during multiple stages of pregnancy. Its role in gestational stages other than term or preterm were the most studied.