A novel costimulatory factor for gamma interferon induction found in the livers of mice causes endotoxic shock

Abstract

Administration of monoclonal anti-CD3 antibody to mice treated with Propionibacterium acnes induced secretion of a high level of gamma interferon (IFN-␥) into the circulation system, while it induced no significant release in untreated mice. In order to analyze this high-level induction of IFN-␥ in these bacterium-treated mice, we investigated the factors that might be involved. An activity that induces IFN-␥ in T cells was observed in the liver extracts of mice treated with P. acnes and subsequently challenged with lipopolysaccharide. Here, we purified an IFN-␥-inducing factor from the liver extract to homogeneity and characterized it. Its molecular mass was 18 to 19 kDa, and its pI was 4.9. The amino acid sequence of the NH 2-terminal portion was determined and shown to have no similarities to any protein in the EMBL, GenBank, and PIR data bases. The same molecule was also demonstrated in the serum factor that was previously reported to have an IFN-␥inducing activity and to have an apparent molecular mass of 75 kDa. Moreover, the activity of this serum factor was recovered in the fraction containing the 18-to 19-kDa protein under reducing conditions and was shown to have the same NH 2-terminal amino acid sequence as that of the factor from the liver extract. In addition to the ability to induce IFN-␥, this protein augmented T-cell proliferation and NK activity in the spleen cells. Thus, several of its biological activities were apparently similar to those of interleukin-12. These results indicated that this novel protein, which exhibited marked costimulatory activity on IFN-␥ production in vitro, was elevated in vivo in response to P. acnes treatment. This factor, probably released from the producing cells by lipopolysaccharide stimuli, may be involved in the high-level induction of IFN-␥ in the P. acnes-treated mice. Recently CD4 ϩ T (Th) cells were divided into distinct subsets according to the profiles of cytokine production (15, 22, 23, 25). This will help our understanding of the regulatory mechanism of immune responses caused by infections with a variety of pathogens. Accessory cells or cytokines produced in response to the initial contact with antigens were shown to exhibit important functions in the development of these cells, depending on the antigenic characteristics. Cells of the Th2 subset are thought to require interleukin-1 (IL-1) or IL-4 for their development (6, 9, 11, 12, 24), and it is shown that IL-12 induces the differentiation of Th1 cells from uncommitted T cells (7, 13, 21). Gamma interferon (IFN-␥), which is produced by activated CD4 ϩ T (Th1), CD8 ϩ T, or NK cells, has been demonstrated to play important roles in cell-mediated immunity. Each of these producer cells may be regulated in the same or different manners, when stimulated. IL-2 was shown to induce IFN-␥ production in NK cells (3, 8), and IL-12 was demonstrated to be involved in IFN-␥ induction in CD4 ϩ T cells or NK cells (7, 13, 21). However, the detailed mechanisms underlying IFN-␥ production as well as the mechanism of devel...

Enhanced induction of dendritic cell maturation and HLA-A*0201-restricted CEA-specific CD8+ CTL response by exosomes derived from IL-18 gene-modified CEA-positive tumor cells

“…First, Exo/IL-18 can chemoattract DC and T cells and thus potentially accumulate these immune cells locally at the sites of administration [16,17]. Secondly, IL-18 contained in Exo/IL-18 may induce the release of IFN-γ, leading to the final elimination of tumor cells [8][9][10][11][12][13]. Thirdly, IL-18 augments the release of IL-2 and promotes T cell proliferation [43], supporting the idea that immune molecules such as IL-18, IFN-γ and IL-2 can influence the local environment in a way that would be beneficial for the patients.…”

“…IL-18, previously identified as IFN-γ-inducing factor, is also a promising vaccine adjuvant [8]. IL-18 elicits a variety of effects on immune response, including stimulating natural killer cells (NK) and T/B lymphocytes to produce high levels of IFN-γ and IL-2 [8,9], promoting T cell proliferation [8,10], enhancing killing activity of cytotoxic T lymphocytes (CTL) and NK cells [11][12][13], facilitating DC maturation [14], exerting pro-inflammatory properties by inducing the release of IL-1β, TNF-α, chemokines [15] and chemoattracting DC, T cells and polymorphonuclear cells [16][17][18]. We and others have previously shown that IL-18 has potent anti-tumor immunity by inducing CD4 + , cytotoxic CD8 + T cells and NK cells [12,13,[19][20][21][22][23], potentiating FasLmediated cytotoxicity and inhibiting tumor angiogenesis [12,24].…”

Canonical and noncanonical inflammasomes in intestinal epithelial cells

“…IL-18 is a classical inducer of IFN-γ, the defining cytokine of Th1 CD4 + T cells (Harrison et al, 2015;Okamura et al, 1995;Robinson et al, 1997;Smeltz, Chen, Hu-Li, & Shevach, 2001). In response to various microbial stimuli, IEC-derived IL-18 may act on Th17 and regulatory CD4 + T cell (Treg) populations, in addition to Th1 cells (Chudnovskiy et al, 2016;Harrison et al, 2015;Smeltz et al, 2001).…”

Overview of interleukin-18: more than an interferon-γ inducing factor

“…Because other cytokines can act as co-stimulants for IFN-␥ production, the failure of neutralizing antibodies to IL-1, IL-4, IL-5, IL-6, or TNF to neutralize the serum activity suggested that it was a distinct factor. In 1995, the third report was published from the same scientists demonstrating that the endotoxin-induced costimulant for IFN-␥ production was present in extracts of livers from mice preconditioned with P. acnes [22]. In this model, the hepatic macrophage population (Kupffer cells) expands dramatically, and in these mice a low dose of bacterial lipopolysaccharide (LPS), which in non-preconditioned mice is not lethal, becomes lethal.…”