Keratinocyte Growth Factor Stimulates Macrophage Inflammatory Protein 3α and Keratinocyte‐derived Chemokine Secretion by Mouse Uterine Epithelial Cells

Abstract

Problem Communication between uterine epithelial cells and the underlying stromal fibroblasts is critical for proper endometrial function. Stromal fibroblast-derived growth factors have been shown to regulate epithelial immune functions. The purpose of this study was to determine whether keratinocyte growth factor (KGF) regulates uterine epithelial cell chemokine and antimicrobial secretion. Method of study Uterine epithelial cells were isolated from Balb/c mice and cultured in either 96-well plates or transwell inserts. Epithelial cells were treated with KGF, epidermal growth factor (EGF), or hepatocyte growth factor (HGF). Macrophage inflammatory protein 3α (MIP3α) and keratinocyte-derived chemokine (KC) levels were measured by ELISA. Results Keratinocyte growth factor stimulated the secretion of MIP3α and KC. The effects on MIP3α by KGF were specific because EGF and HGF had no effect. In contrast, KGF, EGF, and HGF had similar effects on KC. Furthermore, KGF administered to the apical side of epithelial cells had no effect on MIP3α or KC secretion, indicating that the KGF receptor is located on the basolateral surface of uterine epithelial cells. Conclusion We demonstrate that KGF plays a role in uterine epithelial cell secretion of MIP3α and KC, key immune mediators involved in the protection of mucosal surfaces in the female reproductive tract.

Estradiol Regulation of Constitutive and Keratinocyte Growth Factor-Induced CCL20 and CXCL1 Secretion by Mouse Uterine Epithelial Cells

“…Following polarization and formation of tight junctions with high TER, uterine epithelial cells were treated with KGF and/or estradiol (1 × 10 −7 M) for 48 hr. Consistent with previously reported results, 56 when added to polarized cells KGF significantly (p<0.001) stimulated apical and basolateral CCL20 secretion (Figure 3A and 3B). Figure 3 also demonstrates that estradiol inhibited (p<0.001) both apical and basolateral constitutive CCL20 secretion, similar to the findings by Soboll et al 44 In addition, we found that estradiol significantly inhibited KGF-induced apical and basolateral secretion of CCL20 (Figure 3A and 3B).…”

“…56 Others have demonstrated that KGF expression in the FRT fluctuates with stage of the menstrual cycle. 57–59 In the uterus, KGF expression is lowest during the proliferative phase (predominantly estradiol) and highest during the secretory phase (predominately progesterone).…”

Endocrine Regulation of the Mucosal Immune System in the Female Reproductive Tract

“…In contrast, TNF-α and macrophage inhibitory protein (MIP)-3α/CCL20 secretion by uterine ECs is regulated indirectly by fibroblast cell secretion of growth factors such as hepatocyte growth factor (HGF) (Grant-Tschudy and Wira, 2005b). After E 2 treatment, uterine fibroblasts up-regulate the production of HGF, which in turn induces TNF-α and MIP-3α/CCL20 secretion (Grant-Tschudy and Wira, 2005b;Coleman et al, 2009;Haddad and Wira, 2010). E 2 can reduce the proinflammatory cytokine response after stimulation with pathogen ligands (via Toll-like receptors).…”

Innate and adaptive immunity at mucosal surfaces of the female reproductive tract: stratification and integration of immune protection against the transmission of sexually transmitted infections

“…In contrast, the production of some cytokines and chemokines from uterine epithelial cells are regulated indirectly by stromal cell secretion of growth factors. For example, following estradiol treatment, uterine stromal cells up-regulate the production of hepatocyte growth factor (HGF) that in turn regulates TNFα and MIP3α/CCL20 secretion by uterine epithelial cells (Grant-Tschudy and Wira 2005, Coleman et al 2009, Haddad and Wira 2010). …”