Elsevier

Cytokine

Volume 68, Issue 1, July 2014, Pages 65-68
Cytokine

Short Communication
Interleukin-6 and Tumour Necrosis Factor-α differentially regulate lincRNA transcripts in cells of the innate immune system in vivo in human subjects with rheumatoid arthritis

https://doi.org/10.1016/j.cyto.2014.03.004Get rights and content

Highlights

  • lincRNAs are transcripts from non-coding DNA.

  • We found that IL-6 and TNF-α regulate different types of lincRNAs in vivo.

  • Our data suggest a role for lincRNA in the pathophysiology of RA.

  • Our data indicate lincRNAs to be specifically regulated by pharmaceutical agents.

Abstract

lincRNAs recently have been discovered as evolutionary conserved transcripts of non-coding DNA sequences and have been implicated in the regulation of cellular differentiation. In humans, molecular studies have suggested a functional role for lincRNAs in cancer development. The aim of the present study was to examine whether these novel molecules are specifically regulated by different cytokines in cells of the innate immune system in humans in vivo and whether lincRNAs thereby might be involved in the pathophysiology of rheumatoid arthritis (RA). Therefore, CD14+ monocytes were isolated from RA patients before and after anti-IL-6R (tocilizumab) or anti-TNF-α (adalimumab) therapy and lincRNA transcription was analysed by a microarray based experiment. As expected, we found lincRNAs to be present in CD14+ monocytes of RA patients. However, of the total number of 7.419 lincRNAs examined in this study only a very small number was significantly regulated by either IL-6 or TNF-α (85 lincRNAs, corresponding to 1.1%). The numbers of lincRNAs regulated was higher due to TNF-α compared to IL-6. Interestingly, none of the identified lincRNAs was influenced by both, IL-6 and TNF-α, suggesting the regulation of lincRNA transcription to be highly specific for distinct cytokines. Taken together, our results suggest (1) that lincRNAs are novel intracellular molecular effectors of specific cytokines in cells of the innate immune system in humans in vivo and (2) that lincRNAs might be involved in the molecular pathophysiology of RA.

Introduction

For many decades it has been believed that mRNA is only generated from exonic DNA regions encoding for specific proteins. However, in the past few years, several transcripts from non-coding DNA sequences have been identified and referred to as long non-coding RNAs (lncRNA) [1]. These transcripts are also a product of the RNA polymerase II and are capped, spliced and polyadenylated and therefore exhibit similarities to mRNA [2]. lncRNAs can be divided in at least 3 different groups: (1) antisense transcripts from overlapping protein-coding regions (=natural antisense transcripts (NAT)), (2) transcripts from intronic DNA (=intronic lncRNA) and (3) transcripts from inter-gene regions (=intervening non-coding RNA (lincRNA)) [3].

While some initial reports claimed that these novel molecules might be functional irrelevant, several recent molecular studies have implicated a role for lncRNAs in regulation of gene expression [4], genetic imprinting [5] and nuclear organisation [6], [7]. Currently it is thought that more than 8000 lncRNAs exist in the human organism [3]. From a biomedical point of view it is important to note, that dysregulation in lncRNAs have been related to the development of several cancers such as breast cancer [8], colorectal cancer [9] and also melanoma [10]. Beside that, initial reports exist also on non-oncological diseases, e.g. Morbus Alzheimer [11]. Although there is at least also one report on psoriasis as a chronic inflammatory disease [12], to our knowledge, currently no comprehensive report on a potential role of different lincRNAs in rheumatoid arthritis (RA) exists. Also, until now in vivo data on the regulation of lincRNA transcription by different cytokines in cells of the innate immune system in humans are rare. Since these novel molecular regulators might be interesting drug targets for the treatment of chronic inflammatory diseases in the future, we used the present translational research approach in order to examine lincRNA transcription in CD14+ monocytes of RA patients before and after treatment with different antibody based anti-cytokine therapies. CD14+ monocytes were used as a cellular model in the present study since synovial macrophages important in RA pathophysiology are known to generate from these cells [13].

Section snippets

Study population

Ten patients suffering from RA were included into this interventional study. The decision for therapy with either adalimumab or tocilizumab was made according to national guidelines. The study was approved by the local ethics committee and written informed consent was obtained. n = 5 patients were treated with adalimumab (40 mg every 2 weeks, subcutaneously) and n = 5 human subjects with tocilizumab (8 mg/kg body weight every 4 weeks, intraveneously). Mean age of the study population accounted to 56.3 ± 

Results and discussion

lincRNAs, mRNA-like molecules lacking significant protein coding properties, have recently been implicated in many cellular regulatory processes [3]. Within the past few years several studies exhibited a functional role of lncRNAs in cancer development [8], [9], [10]. The aim of the present study was to investigate, whether lncRNAs are specifically regulated by different cytokines in cells of the innate immune system in humans in vivo in the context of RA.

Modern techniques in RNA analysis are

Conclusion

The data obtained in the present study might suggest that lincRNAs may be important intracellular molecular effectors of different cytokines in cells of the innate immune system in humans in vivo in the context of RA.

Acknowledgements

We are particularly grateful to all of the participants in the conducted study for their dedication and contribution to the research. This project was funded by the Federal Ministry of Education and Research (BMBF, No.: 0315540A (FoCus)).

References (16)

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