Cell to Cell Contact Through ICAM-1-LFA-1 and TNF-αSynergistically Contributes to GM-CSF and Subsequent Cytokine Synthesis in DBA/2 Mice Induced by 1,3-β-D-Glucan SCG

Abstract

SCG is a major 6-branched 1,3-beta-D-glucan in Sparassis crispa Fr. showing antitumor activity. We recently found that the splenocytes from naive DBA/1 and DBA/2 mice are potently induced by SCG to produce interferon- gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-12p70 (IL-12p70), and that GM-CSF plays a key biologic role among these cytokines. In this study, we investigated the contribution of cell-cell contact and soluble factors to cytokine induction by SCG in DBA/2 mice. Cell-cell contact involving intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) was an essential step for the induction of GM-CSF and IFN-gamma by SCG but not for the induction of TNF-alpha or IL-12p70 by SCG. SCG directly induced adherent splenocytes to produce TNF-alpha and IL-12p70. GM-CSF was required for the induction of TNF-alpha by SCG, and in turn, TNF-alpha enhanced the release of GM-CSF and thereby augmented the induction of IL-12p70 and IFN-gamma by SCG. Neutralization of IL-12 significantly inhibited the induction of IFN-gamma by SCG. We concluded that induction of GM-CSF production by SCG was mediated through ICAM-1 and LFA-1 interaction, GM-CSF subsequently contributed to further cytokine induction by SCG, and reciprocal actions of the cytokines were essential for enhancement of the overall response to SCG in DBA/2 mice.

Immunological Actions of Sophy β‐Glucan (β‐1,3‐1,6 Glucan), Currently Available Commercially as a Health Food Supplement

“…Of the 6 cell membrane receptors that were blocked by key mAbs to prevent Sophy β-glucan-induced DNA synthesis in cultured PBMCs, CD11a, CD54 and HLAclass II are widely expressed in all lymphoid and myeloid cells and play an important role in the regulation of various immune responses, such as cell proliferation/differentiation and adhesion, and immunoregulatory cytokine production (21,38). In this study, the cell-to-cell contact mechanism(s) underlying the DNA synthesis induced in PBMCs by Sophy β-glucan was investigated using CD11a, CD54 and HLA-class II key mAbs in an inhibition test, because it has been reported previously that cell-to-cell contact involving CD11a (LFA-1), CD54 (ICAM-1) and other cell surface antigens is an essential step in the induction of cytokines, such as granulocyte/macrophage-colony stimulating factor (GM-CSF) and IFN-γ by 6-branched 1,3-beta-Dglucan (SCG) derived from Sparassis crispa (18).…”

Mechanism of Enhanced Hematopoietic Response by Soluble β‐Glucan SCG in Cyclophosphamide‐Treated Mice

“…were induced by SCG in adherent splenocytes alone; on the other hand, IFN-γ induction by SCG required adherent cell-T cell interaction (15). In a previous study, we showed that the leukocyte recovery in CY-treated mice was different for different cell populations, such as granulocytes, macrophages, natural killer cells, B cells and T cells (11,30).…”

“…Recently, we found that GM-CSF is a key molecule for cytokine induction by β-glucan, and that GM-CSF production is specifically induced in DBA/2 mice in vitro (12,14,15). In this study, we investigated the key factors in the cytokine induction by SCG in CY-treated mice, and found that GM-CSF plays an important role in this system.…”

“…We previously reported that naive DBA/2 and DBA/1 mice show high sensitivity to SCG, and the splenocytes from these mice are potently stimulated by SCG to produce cytokines. Recently we found that GM-CSF is a key molecule for cytokine induction by β-glucan, and that GM-CSF is specifically induced by SCG in DBA/2 mice in vitro (12,14,15). In this study, we investigated the key factors in the hematopoietic response induced by SCG in CY-treated mice.…”

“…DBA/2 and DBA/1 mice produce significantly higher titers of antibody to SCG than other inbred naive mice (13). Previously, we reported that interferon-(IFN-) γ, tumor necrosis factor-(TNF-) α interleukin-(IL-) 12p70 and granulocyte-macrophagecolony stimulating factor (GM-CSF) production was not induced by SCG in splenocytes derived from inbred strains of mice, except for DBA/1 and DBA/2 mice, and that GM-CSF was a key molecule among the induced cytokines (12,14,15). These data indicated that GM-CSF is a key molecule for cytokine induction by β-glucan, and that GM-CSF is specifically induced by SCG in DBA/2 mice in vitro.…”