Studies have shown that during late sepsis in mi.ce, there is a profound suppression of TNF-α, IL-1β and IL-6 release by PMφ, SMφ and KC. Such a loss of functional capacity may reduce the animal's ability to ward off infection. Although prolactin (PRL) is known to have an immune enhancing effect on monocytes, T- and B- cells responses under normal conditions, it remains unknown whether PRL has any salutary effect on macrophage (Mφ) cytokine gene expression after sepsis. To study this, C3H/HeN male mice were subjected to polymicrobial sepsis by ce cal 1igation and puncture, then segregated into two groups. One group was treated with ovine PRL (100 μg/25 B.W. subcutaneously) and the other with saline-vehicles. PMφ, SMφ and KC were isolated at 24 h after sepsis. The monolayers were stimulated with or without LPS 10 μg/ml for 1 hour. Total RNA was extracted and cytokine mRNA was detected by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). The results indicate that sepsis markedly decreased the LPS inducible mRNA levels of IL-1β, IL-6 and TNF-α in all three Mφ populations at 24 h compared to shams. However, PRL treatment in vivo following sepsis significantly improved the IL-1β, IL-6 and TNF-α gene expression in all three Mφ populations. Thus, PRL produces beneficial effects on Mφ gene expression which could improve the host immunologie response after sepsis. Since prolactin did not produce any adverse hemodynamic ef fee t s, this agent appears to be a novel and safe immunomodulating hormone for the treatment of immunosuppression during sepsis. (Supported by NIH grants GM 37127 and 53209).