Effect of Granulocytes Colony Stimulating Factor on Decreased IL-12 p40 Production by Chemotherapy.
Authors: Toubai Tomomi , Tanaka Junji , Ota Shuichi , Fukuhara Takashi , Hashino Satoshi , Kondo Takeshi , Morioka Masanobu , Kawamura Tsugumichi , Masauzi Nobuo , Kakinoki Yasutaka , Kobayashi Hajime , Kunieda Yasuyuki , Kasai Masaharu , Kurosawa Mitsutoshi , Imamura Masahiro 
Published: April 2020

Abstract
IL-12 is a cytokine comprised of two disulfide-linked proteins (p35 and p40). The highly coordinated expression of p40 and p35 genes to form IL-12 (also called p70) in the same cell type at the same time is essential for the initiation of effective immuno response. It is known that IL-12 p70 promotes the differentiation of type-1 helper T cells, whereas IL-12 p40 acts as an antagonist of IL-12 p70. Granulocyte-colony stimulating factor (G-CSF) affects the balance in the production of anti-inflammatory cytokines. We had previously examined various cytokine productions (such as IL-4, IL-12, IFN-γ) in Non Hodgkin Lymphoma (NHL) patients. We found that only IL-12 production was associated with the disease status in NHL patients. In the present study, we investigated the plasma IL-12 p40, IL-12 p70 production in patients with B-cell lineage NHL treated with chemotherapy (e.g., CHOP) with or without G-CSF administration. Forty-nine patients were analyzed in this study. Plasma IL-12 p40 and IL-12 p70 were measured separately by enzyme-linked immunosorbent assay (ELISA) before chemotherapy and day 17 after chemotherapy. The survival rates was calculated by the Kaplan-Meier method. Eleven of 49 patients were excluded from this study by the ineligibility. The remaining 38 patients were analyzed in this study. Median age was 61 years old. Clinical stage was I(9), II(10), III(12), IV(7). Eleven patients were received chemotherapy only (C) and 27 patients were received chemotherapy with G-CSF (CG). The patient characteristics in each group were not significantly different. Plasma IL-12 p40 concentration decreased no significantly after chemotherapy than before with G-CSF (median, from 141 pg/ml to 111.1 pg/ml) and without G-CSF (median, from166.9 to 197 pg/ml) (P=0.37). However, median plasma IL-12 p40 concentration decreased significantly after chemotherapy than before chemotherapy with G-CSF (median, from148.4 to 130 pg/ml, P=0.009) and without G-CSF (median, from153.5 to 156.8 pg/ml) (P=0.140) by the classification of each chemotherapy course. Plasma IL-12 p40 concentration in CG group patients with clinical stage III and IV was significantly decreased after chemotherapy than before chemotherapy (median 73.3 pg/ml) compared with C group (0.1 pg/ml)(P=0.006). Plasma IL-12 p70 could not be detected in almost all patients. After chemotherapy, 22 patients showed complete remission (CR), 8 patients showed partial response (PR), 3 patients showed no change (NC), 2 patients showed progressive disease (PD) and 3 patients showed unclear disease status. The overall survival (OS) at 24 months was not significantly differed between both groups(C 64.0% VS GC 89.4%, P=0.67). Interestingly, one of the 2 patients of progressive disease showed high IL-12 p40 concentration in association with disease progression and IL-12 p40 concentration remained high in the other patient. We found that chemotherapy with G-CSF decreased IL-12 p40 production. We did not find the difference in overall survival at the present time, however, a longer administration of G-CSF appears to influence on the survival rate by reducing an immunosuppressive IL-12 p40 production.