1. Joint Public Review:

    The presented manuscript takes a very comprehensive look at the molecular underpinnings of the differential outcomes of IL-27 and IL-6 signaling. Both cytokines engage GP130 as a cellular receptor, however while IL-6 uses homodimers of this signal transducing receptor, IL-27 signals through a heterodimer of GP130 and IL-27Ra. Both receptor complexed lead to the phosphorylation and activation of STAT1 and STAT3 and, hence, to a similar transcriptional program. Strikingly, however, IL-27 responses lean more towards an anti-inflammatory nature (suppressing Th17 and supporting Treg responses), and IL-6 stimulates a classical inflammatory response (inhibiting Treg differentiation, supporting Th17 generation). The presented study deals with elucidating this functional pleiotropy of similar or identical signal transducers.

    The authors follow a comprehensive and elaborated approach, combining in vitro experiments in cell lines and human Th1 cells with (phospho-)proteomics, transcriptome sequencing and mathematical modeling, which gives rise to an impressive data set presented in this manuscript. The large body of experimental work is complemented by mathematical modelling of the signaling pathway(s), which is used to discriminate feasibility of distinct hypothesis in terms of mechanisms behind differential STAT activation.

    The major finding of the study is that IL-27, at least in certain cells (Th-1), leads to the stronger and more sustained activation of STAT1 as compared to IL-6, and that this higher activation of STAT1 is the basis of the differential transcriptional result. The subsequent -omics analyses support differences in signaling outcome between IL-6 and IL-27, and provide an interesting data base for the community. Finally, data re-analysis in a cohort of patients suffering from the autoimmune disease Systemic lupus erythematosus (SLE), reproduced the effects expected by the mathematical model, potentially pointing to differences in their response to different cytokines.

    Overall, the extensive and complex study presents a comprehensive analyses of IL-6 and IL-27 signaling, puzzling together pieces that may have been around before but not put into meaningful context. It provides a compelling overall idea and model of how cytokine receptors make differential use of STAT proteins.

    Read the original source
    Was this evaluation helpful?
  2. Evaluation Summary:

    This study is a great example of an elaborate combination of experimental and mathematical analyses to examine an intriguing, pleiotropic immunological signaling pathway. While a good number of individual aspects of this signaling pathway have been studied and reported before, the present work pieces together many pieces and succeeds to present a conclusive and comprehensive model of this particular cytokine system. The main conclusions are well supported by the presented data and the manuscript will be of interest and relevance for the study of many other cytokine signaling pathways, being of broad relevance for immunologists and cell biologists.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

    Read the original source
    Was this evaluation helpful?