Eriobotrya japonica hydrophilic extract modulates cytokines in normal tissues, in the tumor of Meth-A-fibrosarcoma bearing mice, and enhances their survival time

Abstract

Background: Cytokines play a key role in the immune response to developing tumors, and therefore modulating their levels and actions provides innovative strategies for enhancing the activity of antigen presenting cells and polarizing towards T helper 1 type response within tumor microenvironment. One of these approaches could be the employment of plant extracts that have cytokine immunomodulation capabilities. Previously, we have shown that the Eriobotrya japonica hydrophilic extract (EJHE) induces proinflammatory cytokines in vitro and in vivo.

Methods: The present study explored the in vivo immunomodulatory effect on interferon-gamma (IFN-γ), interleukin-17 (IL-17), and transforming growth factor-beta 1 (TGF-β1) evoked by two water-extracts prepared from EJ leaves in the tissues of normal and Meth-A-fibrosarcoma bearing mice.

Results: Intraperitoneal (i.p.) administration of 10 μg of EJHE and EJHE-water residue (WR), prepared from butanol extraction, increased significantly IFN-γ production in the spleen (p < 0.01) and lung (p < 0.03) tissues at 6-48 hours and suppressed significantly TGF-β1 production levels (p < 0.001) in the spleen for as long as 48 hours. The latter responses, however, were not seen in Meth-A fibrosarcoma-bearing mice. On the contrary, triple i.p. injections, 24 hours apart; of 10 μg EJHE increased significantly IFN-γ production in the spleen (p < 0.02) while only EJHE-WR increased significantly IFN-γ, TGF-β1 and IL-17 (p < 0.03 - 0.005) production within the tumor microenvironment of Meth-A fibrosarcoma. In addition, the present work revealed a significant prolongation of survival time (median survival time 72 days vs. 27 days of control, p < 0.007) of mice inoculated i.p. with Meth-A cells followed by three times/week for eight weeks of i.p. administration of EJHE-WR. The latter prolonged survival effect was not seen with EJHE.

Conclusions: The therapeutic value of EJHE-WR as an anticancer agent merits further investigation of understanding the effect of immunomodulators' constituents on the cellular components of the tissue microenvironment. This can lead to the development of improved strategies for cancer treatment and thus opening up a new frontier for future studies.

Figure 1

IFN-γ, TGF-β and IL-17 production levels in the spleen (A), blood (B) and lungs (C) of mice at 2 hours following administration of 0, 1, 10, and 100 μg EJHE or EJHE-WR (* indicates a significant increase or † indicates a significant decrease in comparison to 0 μg, see text for details).

Figure 2

IFN-γ, TGF-β and IL-17 production levels in the spleen (A), blood (B) and lungs (C) of mice over 48 hours following administration of 10 μg EJHE, EJHE-WR or 2 μg LPS (*: indicates a significant change in comparison to 0 time, see text for details).

Figure 3

Effect of 10 μg EJHE and EJHE-WR on IFN-γ, TGF-β and IL-17 production levels in the spleen (A) and tumor (B) of Meth-A-bearing mice (*: indicates a significant change in comparison to the control, see text for details).

Figure 4

Kaplan-Meier plot of mice inoculated i.p. with 2 × 10⁶ Meth-A cells followed by a three times a week injection of sterile PBS, EJHE (10 μg), or EJHE-WR (10 μg) for eight weeks. Significant prolongation (*p < 0.007) of survival following administration of EJHE-WR-treated Meth-A-bearing mice was observed.