Granulocyte colony-stimulating factor downregulates allogeneic immune responses by posttranscriptional inhibition of tumor necrosis factor- alpha production

Abstract

We report downregulatory effects of granulocyte colony-stimulating factor (G-CSF) on allogeneic immune responses in vitro. G-CSF did not affect the proliferative response of peripheral blood mononuclear cells (PBMC) against allogeneic Daudi cells but did inhibit tumor necrosis factor (TNF)-alpha secretion. In contrast with G-CSF, granulocyte- macrophage (GM)-CSF and interleukin (IL)-3 enhanced alloactivation- induced TNF-alpha production. G-CSF-mediated suppression of TNF-alpha production was not affected by fixation of stimulators. G-CSF did not inhibit TNF-alpha mRNA expression or accelerate mRNA degradation, whereas pentoxifylline inhibited the expression of TNF-alpha mRNA. These results indicate that G-CSF acts directly on responder cells and modulates TNF-alpha production at posttranscriptional levels. Suppression of TNF-alpha secretion was accompanied by an increase of intracellular cyclic adenosine monophosphate (cAMP) concentration in alloactivated PBMC. The cell-permeable cAMP analogue, dibutyryl cAMP, suppressed TNF-alpha secretion without affecting TNF-alpha mRNA expression. G-CSF showed an inhibitory effect on the development of cytotoxic effector cells against allogeneic Daudi cells. Anti-TNF-alpha monoclonal antibody (MoAb) also inhibited the induction of cytolytic activity, and the inhibitory effects of G-CSF and anti-TNF-alpha MoAb on killer activity generation were overcome by adding exogenous TNF- alpha. Hence, impaired generation of cytolytic effector cells by G-CSF is believed to be the result of reduced TNF-alpha production. Collectively, the results described above suggest that G-CSF downregulates allogeneic immune responses by posttranscriptionally inhibiting TNF-alpha production.

Recombinant human granulocyte colony‐stimulating factor protects against MPTP‐induced dopaminergic cell death in mice by altering Bcl‐2/Bax expression levels

“…G-CSF is known to have anti-inflammatory and antiapoptotic effects. Previous studies demonstrated that G-CSF protects against cell death in the non-septic model of ischemia-reperfusion injury and concluded that such a beneficial effect is the consequence of either reduction of tumor necrosis factor-a or inhibition of inducible nitric oxide synthase activity (Gorgen et al 1992;Kitabayashi et al 1995). Moreover, other investigators demonstrated that G-CSF decreased the level of interleukin-1b, interleukin-6, and interleukin-8 in several conditions (Hebert et al 1997;Heard et al 1998;Heard and Fink 1999).…”

Adenosine acts as a chemoprotective agent by stimulating G-CSF production: A role for A1 and A3 adenosine receptors

“…The anti-inflammatory effects of adenosine are attributed mainly to its ability to inhibit TNF production. Kitabayashi et al (Kitabayashi et al, 1995;Wagner et al, 1998) reported that G-CSF inhibited TNF-␣ production. It is suggested that TNF-␣ inhibition by adenosine is mediated by its capability to stimulate G-CSF production.…”

Functional regulation and proteomic characterization of human natural killer cells through recombinant human granulocyte‐colony stimulating factor treatment

“…Several investigations reported that recombinant human rhG-CSF diminished the cytotoxic ability of NK cells [13], altered cytotoxic effectors by IL-2 [14], increased the alloantigen-presenting capability of immune accessory cells [15] and decreased immune function in G-CSF-mobilized blood stem cells harvested from 104 healthy donors [16]. It is thought that the down-regulatory effects of G-CSF may be due to a block in production of TNF-a by the effector cells [17]. However, detailed immunologic effects of rhG-CSF on NK cell activity have not been reported.…”