RNA from LPS‐stirnulated macrophages induces the release of tumour necrosis factor‐α and interleukin‐1 by resident macrophages

Ribeiro, Ronaldo A.; Lucca, Fernando Luiz De; Flores, Carlos A.; Cunha, Fernando; Ferreira, S. H.

doi:10.1155/s0962935193000626

Cited by 9 publications

(2 citation statements)

References 15 publications

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“…The immunological effects observed in lymphocytes [27-29, 31, 101, 126, 127] and macrophages [8,30,106,107] treated with RNAs obtained from lymph nodes of immunized animals with different types of antigens including synthetic peptides of the human immunodeficiency virus type 1 (HIV-1) has been investigated. Recent results indicate that regulatory RNAs are involved in this phenomenon, which is due to the activation of the RNA-dependent protein kinase (PKR) by regulatory RNAs with subsequent activation of the transcription factor NF-κB [29 -31, 127].…”

Section: Introductionmentioning

confidence: 99%

Activation of the RNA-Dependent Protein Kinase (PKR) of Lymphocytes by Regulatory RNAs: Implications for Immunomodulation in HIV Infection

Watanabe

Souza²,

Murad³

et al. 2005

CHR

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It has been known for decades that exogenous RNAs are able to induce cytotoxic T lymphocytes (CTLs) and immunological reactivity to a wide variety of antigens. The molecular events responsible for these effects remain unclear for more than two decades. It has been decided to revisit this phenomenon in the light of new concepts that are just emerging in Molecular Biology, such as the regulation of gene expression by noncoding RNAs, named regulatory RNAs. The immunological effects observed in lymphocytes treated with RNAs obtained from lymph nodes of immunized animals with different types of antigens including synthetic peptides of the human immunodeficiency virus type 1 (HIV-1) have been investigated. Our recent results showed that regulatory RNAs are involved in this phenomenon, which is due to the activation of the RNA-dependent protein kinase (PKR) by regulatory RNAs with subsequent activation of the transcription factor NF-kappaB. The RNA-dependent protein kinase (PKR) is a serine/threonine kinase and contains two RNA-binding domains (RBD-I and RBD-II) within the N-terminal region. PKR is activated by viral double-stranded RNA (dsRNA) and highly structured single-stranded RNAs. This review will focus on the structure and functions of PKR including its role in HIV-1 infection. Special emphasis will be placed on a regulatory RNA, named p9-RNA, isolated from lymphocytes of animals immunized with the synthetic peptide p9 (pol: 476-484) of HIV-1. It was found that the regulatory p9-RNA induces CTLs and production of IFN-gamma. These findings showed for the first time that transcriptional control of gene expression by a regulatory RNA can be mediated by PKR through the activation of the transcription factor NF-kappaB. A model for the mechanism of action of the regulatory p9-RNA responsible for the production of IFN-gamma is proposed. Elucidating the molecular mechanism of p9-RNA may contribute to determining the rationale for the use of this regulatory RNA as an immunomodulator in HIV-infected patients.

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Section: Introductionmentioning

confidence: 99%

Activation of the RNA-Dependent Protein Kinase (PKR) of Lymphocytes by Regulatory RNAs: Implications for Immunomodulation in HIV Infection

Watanabe

Souza²,

Murad³

et al. 2005

CHR

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“…The presence of these cytokines in the supernatants of LPS-stimulated macrophages used to prepare MNF has been described. 15,16 The possibility that MNF activity results from the combination of these three cytokines was tested by injection of different concentrations of these cytokines alone or in combination into the abdominal cavity of mice. Although IL-1, IL-8 and TNF-a injected singly at high doses were unable to promote a signi cant nociception in mice, injection in combination reproduced the MNF-induced nociception.…”

Section: Discussionmentioning

confidence: 99%

Tumor necrosis factor, interleukin‐1 and interleukin‐8 mediate the nociceptive activity of the supernatant of LPS‐stimulated macrophages

Thomazzi

Ribeiro

Campos

et al. 1997

Mediators of Inflammation

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It has been suggested that the supernatant of LPSstimulated macrophages (macrophage nociceptive factor, MNF) promotes nociception in mice. Intraperitoneal administration of MNF induced dose-related writhing, which reached a plateau between 18 and 26 min after injection and decreased within 60 min. The release of MNF was inhibited by the pretreatment of the macrophages with cycloheximide, a protein synthesis inhibitor, or with the glucocorticoid dexamethasone. Cyclooxygenase inhibitors, such as indomethacin or paracetamol, had no effect. The MNF-induced nociception was inhibited in a dose-related manner by pretreatment of the animals with indomethacin, paracetamol or dexamethasone. Pretreatment of the animals with the sympatholytics guanethidine and atenolol partially reduced the MNF nociception, which was abolished by the combination of guanethidine or atenolol with indomethacin. The preincubation of MNF with antisera against TNF-α, IL-1 or IL-8 partially inhibited its nociceptive effect. Intraperitoneal injection of a mixture of the recombinants cytokines TNF-α, IL-1 and IL-8 mimicked MNF nociception. The individual injection of these cytokines was unable to induce the nociceptive effect. In conclusion, our data suggest that the nociceptive activity of the supernatant of LPSstimulated macrophages is explained by the presence of TNF-α, IL-1 and IL-8, the nociceptive activity of which (in mice) seems to be due to the release of cyclooxygenase and sympathetic metabolites.

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Partial characterization of the RNA from LPS-stimulated macrophages that induces the release of chemotactic cytokines by resident macrophages

et al. 1995

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It is well established that exogenous RNA is incorporated into eukaryotic cells and is able to exert various biological responses. Little, however, is known about the effects of such RNA on macrophages. In this study, we demonstrate that RNA extracted from macrophages stimulated with Escherichia coli lipopolysaccharide (LPS), referred to as L-RNA, in contrast to RNA from non-stimulated macrophages (N-RNA), induces the release of a macrophage-derived neutrophil chemotactic factor (MNCF) and interleukin-8 (IL-8) from macrophage monolayers. The effect of L-RNA was dependent of the integrity of the polynucleotide chain and was not due to LPS contamination since its ability to induce MNCF and IL-8 release was strongly reduced by RNase but was not affected by DNase or polymyxin B. The poly A(+)L-RNA and poly A(-)L-RNA fractions were able to induce the release of MNCF and IL-8, indicating that the L-RNA could be acting at transcriptional and translational levels. The demonstration that actinomycin-D and cycloheximide inhibited the release of MNCF and IL-8 by L-RNA-stimulated macrophages confirms this assumption. Fractionation of the total L-RNA by centrifugation on a 5-20% sucrose gradient showed that the L-RNA which sediments in the 4-5S region of the gradient is the only fraction capable of inducing the release of MNCF from naive macrophages. We have previously shown that macrophage monolayers stimulated with interleukin-1 beta or LPS release a low molecular RNA which also sediments in the same 4-5S region. Taken together, these results support our proposal that resident macrophages, when activated by injurious stimuli, in addition to secreting cytokines, also release a low molecular weight (4-5S) RNA which may act on the surrounding macrophages to further stimulate the release of cytokines. This process would amplify the inflammatory response and would increase the mechanisms involved in the defense response or tissue injury.

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RNA from LPS‐stirnulated macrophages induces the release of tumour necrosis factor‐α and interleukin‐1 by resident macrophages

Cited by 9 publications

References 15 publications

Activation of the RNA-Dependent Protein Kinase (PKR) of Lymphocytes by Regulatory RNAs: Implications for Immunomodulation in HIV Infection

Activation of the RNA-Dependent Protein Kinase (PKR) of Lymphocytes by Regulatory RNAs: Implications for Immunomodulation in HIV Infection

Tumor necrosis factor, interleukin‐1 and interleukin‐8 mediate the nociceptive activity of the supernatant of LPS‐stimulated macrophages

Partial characterization of the RNA from LPS-stimulated macrophages that induces the release of chemotactic cytokines by resident macrophages

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