Keeping each other in check: A reciprocal relationship between cytokines and miRNA

Cytokines are a large group of secreted messenger molecules that are produced by different cell types, including cells of the immune system and tumor cells. Cytokine signaling is necessary for successfully mounting as well as dissolving an immune response. Cytokines signal through their specific receptors. Signal transduction from these receptors happens through the JAK/STAT pathway that recently celebrated its 20th anniversary of discovery. The activation of a kinase (JAK1, JAK2, JAK3, or TYK2) downstream of the cytokine receptor results in phosphorylation and dimerization of the STAT transcription factors (STAT1–4, STAT5A, STAT5B, and STAT6) that translocate to the nucleus and regulate transcription of their target genes. Apart from transcriptional regulation, cytokine signaling is regulated through feedback loops by the STAT targets themselves, e.g., suppressor of cytokine signaling (SOCS) proteins or interleukin receptors (as reviewed in ref. 1). In chronic inflammation, autoimmune diseases as well as cancer aberrant cytokine signaling are often observed. In this regard, in chronic skin inflammation, T cells from psoriatic skin lesions display hypersensitivity for IFNα with enhanced STAT3 signaling due to a deficiency in SOCS3. Likewise, malignant T cells in skin lesions from mycosis fungoides (the most common form of cutaneous T-cell lymphoma [CTCL]) become resistant to IFNα due to an aberrant expression of SOCS3.^2-4

In the last couple of years, however, yet another layer of cytokine regulation is being unraveled: miRNAs. miRNAs are small non-coding RNAs that can bind to the 3′UTR of mRNAs of cytokines or that of other signaling components, thereby inhibiting their translation. Two important examples are miR-155, a major oncogenic miRNA that targets SOCS1, as well as miR-203, a skin-specific miRNA that targets SOCS3 (as reviewed in ref. 5).

Although so far virtually overlooked, the regulatory relationship between cytokines and miRNA seems to be reciprocal: not only do miRNAs target cytokine mRNA, and thereby regulate cytokine expression, the cytokine signaling has likewise an impact on miRNA expression. Thus, it seems crucial to investigate how altered cytokine patterns, as for instance in inflammation and cancer, influence miRNA expression patterns. In this regard, Kopp et al., in an exciting study recently published in Cell Cycle⁶ describe what drives the aberrant expression of miR-155 found in CTCL.⁷ They show that expression of BIC (the host gene of miR-155) is induced by the IL-2Rβγ cytokines IL-2 and IL-15 via activation of transcription factor STAT5. Apart from the cytokine-dependent expression and the direct induction by constitutive STAT5 activity as shown in this study, miR-155 has previously been described to be induced by inflammatory cytokines such as TNFα, IFNγ, or IL-1β, all of which play a key role in inflammation and cancer via STAT1 or NFkB signaling. miR-155 is just one of several major oncogenic miRNAs that are aberrantly expressed in many cancers. Several of these oncomiRs have been described to be regulated via cytokine-mediated STAT signaling. Thus, miR-21 and the miR-17–92 cluster are regulated by STAT3,^5,8 which, in turn, is activated by different cytokines, e.g., IL-6 or IL-21. Importantly, deregulated IL-6 and IL-21 signaling as well as miR-21 and miR17–92 expression has additionally been observed in different inflammatory diseases.

Through the large body of data describing miRNA function that has been produced throughout the last years we have learned that miRNAs represent an important network of fine-tuners that add an additional layer of control of gene expression. It has become very clear that aberrant miRNA expression adds a substantial contribution to the development of many different pathogenic settings. However, much still needs to be learned about the reciprocal relationship of cytokines and miRNAs in the orchestration of inflammation and disease.

Kopp KL, Ralfkiaer U, Gjerdrum LM, Helvad R, Pedersen IH, Litman T, et al. STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma. Cell Cycle. 2013;12:1939–47. doi: 10.4161/cc.24987.