Recombinant human prolactin improves antitumor effects of murine natural killer cells in vitro and in vivo.
OBJECTIVE
To verify the effect of prolactin on natural killer (NK) cells in vivo and its implications for NK cell immunotherapy.


METHODS
Recombinant human prolactin (rhPRL; 30 microg, i.p.) was administered to BALB/c mice and severe combined immunodeficiency (SCID) mice 1 day before harvesting splenocytes for (51)Cr release assay to examine the effects of rhPRL on NK cells of normal mice. rhPRL (10 microg, i.p., every other day for a total of 5 injections) was administered to BALB/c mice after syngeneic bone marrow transplantation (SBMT) to determine its effects on NK cell reconstitution. CT26 tumor cells were injected into BALB/c mice intravenously on day 0, and interleukin (IL)-15-cocultured activated syngeneic NK cells (IL-15-NK) from SCID mice were intravenously injected into tumor-bearing BALB/c mice on day 1. The improvement of antimetastasis effects and survival of tumor-bearing mice by rhPRL were checked.


RESULTS
BALB/c and SCID mice receiving one rhPRL injection exhibited a significant increase in cellular cytotoxicity against YAC-1 target tumor cells; the specific lysis was enhanced from 12.5 to 17.3% in BALB/c mice and from 27.8 to 51.2% in SCID mice. BALB/c mice continuously receiving rhPRL injections exhibited significant increases in NK cell (DX5-positive) contents and cellularity in both the bone marrow and spleen in the SBMT model. The bone marrow NK cell contents were improved from 1.53 to 3.13% after rhPRL injection. NK cells from SCID mice were then cultured with recombinant human IL-15 (rhIL-15; 6000 IU/ml), rhPRL (10 ng/ml) or rhIL-15 plus rhPRL for 25 days. The cytotoxicity and cellularity were enhanced by rhPRL when tested on day 10, when comparing the rhIL-15 plus rhPRL group with the rhIL-15 group or rhPRL group, respectively. In the adoptive cellular immunotherapy study, the IL-15-NK plus IL-15 plus rhPRL group showed significantly lower numbers of lung metastases and longer survival than the IL-15-NK plus IL-15 group; the mean survival interval was prolonged from 31.5 to 53.7 days.


CONCLUSIONS
These results indicate that rhPRL is possibly an important regulator of NK cells and a potential biologic product for immunotherapy.
Sun
Rui
R
School of Life Sciences, University of Science and Technology of China, Hefei City, China.
Wei
Haiming
H
Zhang
Jianhua
J
Li
Ailing
A
Zhang
Weici
W
Tian
Zhang
Z
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D019409:Interleukin-15 / Q000494:pharmacology / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D011388:Prolactin / Q000494:pharmacology* / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D015996:Survival Rate; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation
D019409:Interleukin-15; D011993:Recombinant Fusion Proteins; D011388:Prolactin