In Vitro Development of Bone‐Marrow‐Derived Macrophages Influence of Mouse Genotype on Response to Colony‐Stimulating Factors and Autocrine Interferon Induction

Kruse, Andrea; Kirchner, Holger; Zawatzky, Rainer; Domke‐Opitz, I.

doi:10.1111/j.1365-3083.1989.tb02483.x

Cited by 5 publications

(5 citation statements)

References 45 publications

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“…These observations are consistent with previous studies describing IFN-a as a key cytokine in the pathogenesis of SLE [12-19, 24, 25]. Failure to detect IFN-a protein in serum by bioassay or ELISA, whereas the IFN-inducible gene IFRG28 could be detected within CD11b + cells by RT-PCR amplification, suggest that IFN-a is produced locally in an auto-or paracrine manner [26].…”

Section: Discussionsupporting

confidence: 92%

Elevated levels of endogenous apoptotic DNA and IFN‐α in complement C4‐deficient mice: Implications for induction of systemic lupus erythematosus

et al. 2007

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Systemic lupus erythematosus (SLE), an autoimmune disease characterized by chronic nephritis, arthritis and dermatitis, and the presence of antinuclear autoantibodies, is associated with complement factor deficiencies in the classical activation pathway. In addition, IFN-a seems to be a key cytokine in SLE as an activated IFN-a system is regularly observed in patients with SLE. Here, we demonstrate that in lupus-susceptible, complement C4-deficient mice the lack of complement results in elevated intravascular levels of apoptotic DNA. The apoptotic DNA is targeted to the splenic marginal zone where it accumulates and induces IFN-a. As such, we present here a unifying hypothesis for the induction of SLE that incorporates the role of complement deficiency and elevated levels of IFN-a. IntroductionSystemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by autoantibodies against various nuclear antigens, as well as the generation of immune complexes (IC) leading to inflammatory responses in skin, kidneys, joints, the vasculature and the heart [1]. Susceptibility genes for SLE include those involved in the deficiency of early complement factors of the classical pathway (C1, C4, C2) [2], which has been confirmed in animal models for complement deficiency [3,4]. Current explanations for the loss of tolerance in states of complement deficiency include impaired elimination of apoptotic bodies [4,5] or dying cells [6] as a source of autoantigens [7,8], and inadequate regulation of follicular B cells via the complement receptor CD21/35 [3], although the absence of CD21, or its most important ligand (C3d), does not seem to be associated with SLE [9,10]. As such, neither model alone can adequately account for the association of complement deficiency and SLE [11].IFN-a is another important factor in the development of SLE, and elevated levels of this antiviral cytokine or IFN-a-induced genes are frequently observed in patients with SLE [12][13][14][15]. Activation of the class I IFN system has been confirmed by recent studies using microarray approaches [16][17][18][19]. Moreover, the administration of IFN-a for therapeutic purposes induces typical SLE autoantibodies as a side effect [20,21]. Both these phenomena are poorly understood and no unifying hypothesis, incorporating the role of complement deficiency and elevated IFN-a levels in the induction of SLE, exists. Recently, we described an unusual deposition of IgMcontaining immune complexes (IgM-IC) in the splenic marginal zone (MZ) of complement C4-deficient (C4 null ) mice. This IgM-IC deposition led to restoration of a humoral immune response against foreign antigens within those IC, when compared to mice receiving antigen only [22]. Murine MZ macrophages are known to produce IFN-a [23] and we hypothesized that intravascular nuclear antigen levels would be elevated as a result of complement deficiency and that natural IgM anti-DNA antibodies would mediate the IC deposition in the splenic MZ. Here, the nuclear antigens would induce IFN-a, which i...

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Section: Discussionsupporting

confidence: 92%

Elevated levels of endogenous apoptotic DNA and IFN‐α in complement C4‐deficient mice: Implications for induction of systemic lupus erythematosus

et al. 2007

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“…Detection of endogenous IFN in cultures of BMM in the presence of M-CSF. In cultures of BMM, endogenous IFN is secreted constitutively in low amounts, and mostly its detection has been possible only by indirect means, i.e., induction of IFN-induced OASE or establishment of an antiviral state (23,29,36,37). When we compared IFN levels in culture supernatants from C57BL/6, BALB/c, and B6.C-H28c macrophages, we observed significant differences in that BALB/c macrophages consistently secreted between 12 and 54 IU of IFN whereas macrophages from the two other strains produced low-to-undetectable amounts ( Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…(ii) Induction of OASE activity. It has been shown that endogenous IFN is responsible for elevated levels of OASE in cultures of BMM (23,29,37). In view of the observed differences in endogenous IFN levels, we also determined the levels of OASE in BMM from all three of the mouse strains under study.…”

Section: Resultsmentioning

confidence: 99%

Endogenous interferon specifically regulates Newcastle disease virus-induced cytokine gene expression in mouse macrophages

Zawatzky

Wurmbaeck

Falk

et al. 1991

J Virol

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In macrophages from inbred mice, the magnitude of the interferon (IFN) response to Newcastle disease virus (NDV) infection is under genetic control of the If-1 locus, which carries the allele for either high (h) or low (l) IFN production. Here, we report that the activity of genes within the If-1 locus is influenced by macrophage-derived endogenous IFN. In addition to various other biological effects, we observed that endogenous IFN specifically downregulated NDV-induced IFN and interleukin 6 production. Preculture of bone marrow-derived macrophages (BMM) from BALB/c (If-1l) mice in macrophage colony-stimulating factor plus anti-IFN-beta provoked a 30- to 50-fold increase in NDV-induced cytokine production compared with induced control cultures in macrophage colony-stimulating factor alone, whereas only a 4- to 6-fold increase was observed in anti-IFN-beta-treated BMM from C57BL/6 (If-1h) mice. This resulted in nearly complete abrogation of the genetically determined difference in the response to NDV. The increase was specific for NDV and was marked by strong additional activation of IFN-alpha genes. Studies using BMM from B6.C-H28c If-1l congenic mice gave results identical to those obtained with BALB/c BMM. Addition of 20 IU of recombinant IFN-alpha 4 to anti IFN-beta-treated macrophages from B6.C-H28c mice 20 h prior to NDV infection strongly downregulated the IFN-alpha, IFN-beta, and interleukin 6 responses. The genetic difference between macrophages from If-1h and If-1l mice was thus reestablished, since the same treatment caused only weak reduction of NDV-induced cytokine gene expression in BMM from C57BL/6 mice. These data suggest that the If-1h and If-1l alleles harbor IFN-inducible genes that, following activation, specifically suppress subsequent cytokine gene expression in response to NDV.

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“…induction of the IFN-induced enzyme 2',5'-oligoadenylate synthetase (OASE) or establishment of an antiviral state [5,[12][13][14], When we compared IFN levels in culture supernatants from C57BL/6, BALB/c and B6.C-H28C macrophages, we observed significant differences in that BALB/c macro phages consistently secreted between 12 and 54 IU of IFN whereas macrophages from C57BL/6 and the con genic line produced low to undetectable amounts. This suggests that the amount of endogenous IFN secreted from macrophages is under genetic control.…”

Section: Detection O F Endogenous Ifn In Cultures O F Mouse Bmmtp In mentioning

confidence: 99%

Regulation by Endogenous Interferon of Virus-Induced Cytokine Gene Expression in Mouse Macrophages

Zawatzky

Homfeld²

1991

Pathobiology

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In macrophages from inbred mice the magnitude of the interferon (IFN) response to Newcastle disease virus (NDV) infection is under genetic control of the locus If-1, with C57BL/6 carrying the ‘high-producer’ allele If-l^h whereas BALB/c have the ‘low-producer’ allele If-1¹. The IFN produced consists of 90% IFN-β and there are 10-fold differences between macrophages from If-l^h and If-1¹ mice. Recently, we observed that interleukin-6 (IL-6) is coinduced by NDV in macrophages and seems to be under the same genetic control. Noninduced macrophages have been shown to secrete low amounts of antiviral activity endogenously when cultured in the presence of the macrophage-colony-stimulating factor (M-CSF). Here, we report that the amount of this endogenous IFN varies between macrophages from different mouse strains. Macrophages from BALB/c were found to secrete 5–10 times more endogenous IFN compared to C57BL/6. The antiviral activity could be identified as IFN-β. Interestingly, we observed that endogenous IFN specifically down-regulates NDV-induced IFN and IL-6 production. Preculture of BALB/c macrophages in M-CSF plus anti-IFN-β to neutralize the biological effects of the endogenous IFN provoked a 30- to 50-fold increase in NDV-induced cytokine production, resulting in a nearly complete abrogation of the genetically determined difference since the same treatment only caused a 6-fold increase in C57BL/6 macrophages following NDV infection. This increase in cytokine gene expression was specific for NDV and marked by a strong additional activation of IFN-α genes. Addition of mouse recombinant IFN-α₄ to anti-IFN-β-treated macrophages for 18 h prior to NDV infection down-regulated again IFN gene expression and reestablished the genetic differences between macrophages from If-l^h and If-1¹ mice. Studies using macrophages from B6.C-H28^C congenic mice, carrying the histocompatibility locus H-28 and the If-1¹ locus from BALB/c on a C57BL/6 background, gave identical results as with BALB/c macrophages. These data indicate that the two alleles If-l^h and If-1¹ may harbor IFN-inducible genes responding differently to IFN and specifically suppressing subsequent IFN and IL-6 gene expression after stimulation by NDV.

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In Vitro Development of Bone‐Marrow‐Derived Macrophages Influence of Mouse Genotype on Response to Colony‐Stimulating Factors and Autocrine Interferon Induction

Cited by 5 publications

References 45 publications

Elevated levels of endogenous apoptotic DNA and IFN‐α in complement C4‐deficient mice: Implications for induction of systemic lupus erythematosus

Elevated levels of endogenous apoptotic DNA and IFN‐α in complement C4‐deficient mice: Implications for induction of systemic lupus erythematosus

Endogenous interferon specifically regulates Newcastle disease virus-induced cytokine gene expression in mouse macrophages

Regulation by Endogenous Interferon of Virus-Induced Cytokine Gene Expression in Mouse Macrophages

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