Analysis of human blood monocyte activation at the level of gene expression. Expression of alpha interferon genes during activation of human monocytes by poly IC/LC and muramyl dipeptide.

Stevenson, Henry C.; Dekaban, Gregory A.; Miller, Paul J.; Benyajati, Cheeptip; Pearson, Mark

doi:10.1084/jem.161.3.503

Cited by 31 publications

(6 citation statements)

References 25 publications

(24 reference statements)

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“…In contrast, monocytes incubated with exogenous poly(I:C) displayed elevated levels of IFN-␤, CXCL10, IFIT1 (Fig. 1B), IFN-␣, G1P2/ISG15, PKR, and IRF7 (data not shown), in agreement with previous information (40). Similarly, neutrophils incubated with LPS or IFN-␤ were found to accumulate elevated transcript levels of TNF-␣ and IL-12p40, or IFIT1, ISG15, PKR, and IRF7, respectively (Fig.…”

Section: Resultssupporting

confidence: 81%

Activation of an Immunoregulatory and Antiviral Gene Expression Program in Poly(I:C)-Transfected Human Neutrophils

Tamassia

Moigne

Rossato

et al. 2008

The Journal of Immunology

106

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Neutrophils, historically known for their involvement in acute inflammation, are also targets for infection by many different DNA and RNA viruses. However, the mechanisms by which they recognize and respond to viral components are poorly understood. Polyinosinic:polycytidylic acid (poly(I:C)) is a synthetic mimetic of viral dsRNA that is known to interact either with endosomal TLR3 (not expressed by human neutrophils) or with cytoplasmic RNA helicases such as melanoma differentiation-associated gene 5 (MDA5) and retinoic acid-inducible gene I (RIG-I). In this study, we report that intracellularly administered poly(I:C) stimulates human neutrophils to specifically express elevated mRNA levels encoding type I IFNs, immunoregulatory cytokines, and chemokines, such as TNF-α, IL-12p40, CXCL10, CXCL8, CCL4, and CCL20, as well as classical IFN-responsive genes (IRG), including IFIT1 (IFN-induced protein with tetratricopeptide repeats 1)/IFN-stimulated gene (ISG)56, G1P2/ISG15, PKR (dsRNA-dependent protein kinase), and IFN-regulatory factor (IRF)7. Investigations into the mechanisms whereby transfected poly(I:C) promotes gene expression in neutrophils uncovered a crucial involvement of the MAPK-, PKR-, NF-κB-, and TANK (TNF receptor-associated NF-κB kinase)-binding kinase (TBK1)/IRF3-signaling transduction pathways, as illustrated by the use of specific pharmacological inhibitors. Consistent with the requirement of the cytoplasmic dsRNA pathway for antiviral signaling, human neutrophils were found to constitutively express significant levels of both MDA5 and RIG-I, but not TLR3. Accordingly, neutrophils isolated from MDA5-deficient mice had a partial impairment in the production of IFN-β and TNF-α upon infection with encephalomyocarditis virus. Taken together, our data demonstrate that neutrophils are able to activate antiviral responses via helicase recognition, thus acting at the frontline of immunity against viruses.

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Section: Resultssupporting

confidence: 81%

Activation of an Immunoregulatory and Antiviral Gene Expression Program in Poly(I:C)-Transfected Human Neutrophils

Tamassia

Moigne

Rossato

et al. 2008

The Journal of Immunology

106

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“…Macrophages can produce biologically active molecules when activated by MDP in vitro. These include IFN-y, tumor necrosis factor, differentiation-stimulating factor, colonystimulating factors, and fibroblast growth factor [1,5,21,26]. Some analogues of MDP stimulate macrophages to produce lymphocyte-activating factor properties [6] and no detectable endogenous pyrogen activity [3].…”

Section: Discussionmentioning

confidence: 99%

Immunomodulatory and therapeutic properties of FK-565 in mice

Talmadge¹,

Lenz²,

Schneider³

et al. 1989

Cancer Immunol Immunother

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The heptanoyl tripeptide, FK-565 is a biological response modifier with potent therapeutic properties for the treatment of experimental and spontaneous metastases. Doses of FK-565 greater than 5 mg/kg are required for in vivo augmentation of natural killer cells, macrophages, and for therapeutic activity, presumably because FK-565 is a peptide small molecular mass which is rapidly degraded and excreted. Optimal therapeutic activity is observed at approximately 25-50 mg/kg FK-565, administered i.v. three times per week for 4 weeks. In addition to its therapeutic properties, which were consistently greater than the positive control at optimal doses, FK-565 had significant immunoaugmentary properties for natural killer cells, macrophages, and T cells both in vitro and in vivo, suggesting that its therapeutic activity is due to immune augmentation.

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“…For instance, y-11" and interleukin-2 (IL-2), which are T cell lymphokines, and a-IFN, which is produced by activated macrophages (19,20), are present only in very small quantities (12). Of great interest is the fact that the synovium is still capable of producing lymphokines when stimulated by PHA.…”

Section: Discussionmentioning

confidence: 99%

“…Hence, the paradox of the synovium is that it contains T cells and macrophages, which, by pheno- typic criteria, are considered activated (i.e., HLA-DR positive and/or Tac positive) (14-18), but does not secrete the usual products of activation. For instance, y-11" and interleukin-2 (IL-2), which are T cell lymphokines, and a-IFN, which is produced by activated macrophages (19,20), are present only in very small quantities (12). Of great interest is the fact that the synovium is still capable of producing lymphokines when stimulated by PHA.…”

Section: Discussionmentioning

confidence: 99%

Peripheral blood and synovial fluid monocyte activation in inflammatory arthritis. ii. low levels of synovial fluid and synovial tissue interferon suggest that γgm‐interferon is not the primary macrophage activating factor

Firestein

Zvaifler

1987

Arthritis & Rheumatism

161

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Because synovial fluid monocytes (SFM) in patients with inflammatory arthritis bear an activated phenotype (i.e., high expression of HLA-DR and low expression of the monocyte differentiation antigen Mo2), we a,ssessed the role of y-interferon (y-IFN) in the activation of these cells. Sensitive and specific radioimmunoassays detected only 0.40 k 0.20 unitdm1 of y-IFN in the SF of patients with rheumatoid arthritis (RA) and 0.61 :& 0.67 unitdm1 of yIFN in the SF of patients with other forms of chronic inflammatory arthritis. There was no detectable a-IFN in any SF studied by radioimmuinoassay. Bioassays failed to detect nonimmunoreactive IFN. Synovial tissue (ST) explants produced very little yIFN (0.14 f 0.091 unitdml), and production was not increased by the presence of indomethacin in the cultures or by removal of adherent cells. However, y-IFEI was produced if ST was cultivated in the presence of phytohemagglutinin. In SF and ST supernatants, y-IFM-mediated induction of HLA-DR on monocytes was inhibited, even though the amount of immunoreactive IFN was not affected. Prostaglandin E2 was shown to be one possible inhibitor. We demonstrated that a factor that induces HLA-DR on some ihdividuals' peripheral blood monocytes, and cannot be neutralized by monoclonal anti-y-IFN antibody, is present in SF and ST supernatants. These data suggest that activation of SFM may occur by mechanisms other than y-IFN.In the work described in the companion paper (l), synovial fluid monocytes (SFM), but not peripheral blood monocytes (PBM), from patients with inflammatory arthritis were demonstrated to have an activated phenotype. This phenotype was defined by studying the expression of certain surface antigens on resting and y-interferon (y1FN)-treated PBM in normal individuals (2). In the resting state, monocytes express small quantities of class 11 major histocompatibility complex antigens and large quantities of monocyte differentiation antigens (MAg), such as Mo2 and 63D3. In contrast, interferon-activated cells display considerable HLA-DR on their surface, but comparatively little MAg.Because the phenotype of SFM resembled that of PBM exposed to y-IFN, we believed that this lymphokine was probably the primary macrophage activating factor in the synovium and synovial fluid. Hence, we measured a-IFN and y-IFN levels in synovial fluid. In addition, y-IFN production by rheumatoid synovium was assessed. To our surprise, very little interferon was found in either case, which suggests that other signals may activate SFM.

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Analysis of human blood monocyte activation at the level of gene expression. Expression of alpha interferon genes during activation of human monocytes by poly IC/LC and muramyl dipeptide.

Cited by 31 publications

References 25 publications

Activation of an Immunoregulatory and Antiviral Gene Expression Program in Poly(I:C)-Transfected Human Neutrophils

Activation of an Immunoregulatory and Antiviral Gene Expression Program in Poly(I:C)-Transfected Human Neutrophils

Immunomodulatory and therapeutic properties of FK-565 in mice

Peripheral blood and synovial fluid monocyte activation in inflammatory arthritis. ii. low levels of synovial fluid and synovial tissue interferon suggest that γgm‐interferon is not the primary macrophage activating factor

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