The present study investigated the ability of surfactant associated protein A1 (SFTPA1), a major component of lung surfactant, to bind and serve as a signal in human cultured myometrial cells. By using ligand blot analysis with 125I-SFTPA1, we consistently identified two myometrial SFTPA1 interacting proteins (55 and 200 kDa). We found that the SFTPA1 immunoreactive protein was present in myometrial cells. We also showed by indirect immunofluorescence the nuclear translocation of RELA (also known as NFkappaB p65 subunit) after activation of myometrial cells by SFTPA1. Neutralization of TLR4 did not reverse this effect. Moreover, SFTPA1 rapidly activated mitogen-activated protein kinase 1/3 (MAPK1/3) and protein kinase C zeta (PRKCZ). The prolonged treatment of myometrial cells with SFTPA1 upregulated PTGS2 (COX2) protein levels. We next evaluated whether SFTPA1 affected the actin dynamic. Stimulation of myometrial cells with SFTPA1 markedly enhanced the intensity of the filamentous-actin pool stained with fluorescein isothiocyanate-phalloidin. Inhibition of PRKC or Rho-associated, coiled-coil containing protein kinase 1 (ROCK) reduced the SFTPA1-mediated stress fiber formation. Our data support the hypothesis that human myometrial cells express functional SFTPA1 binding sites and respond to SFTPA1 to initiate activation of signaling events related to human parturition.