Inflammatory cytokines are fundamental mediators of the organismal response to injury, infection, or other harmful stimuli. To elucidate the early and mostly direct transcriptional signatures of inflammatory cytokines, we profiled all immunologic cell types by RNAseq after systemic exposure to IL1β, IL6, and TNFα. Our results revealed a significant overlap in the responses, with broad divergence between myeloid and lymphoid cells, but with very few cell-type-specific responses. Pathway and motif analysis identified several main controllers (NF-κB, IRF8, and PU.1), but the largest portion of the response appears to be mediated by MYC, which was also implicated in the response to γc cytokines. Indeed, inflammatory and γc cytokines elicited surprisingly similar responses (∼50% overlap in NK cells). Significant overlap with interferon-induced responses was observed, paradoxically in lymphoid but not myeloid cell types. These results point to a highly redundant cytokine network, with intertwined effects between disparate cytokines and cell types.
Early transcriptional effects of inflammatory cytokines reveal highly redundant cytokine networks
Disclosures: The authors declare no competing interests exist.
Immunological Genome Project Consortium members: Dughan Ahimovic, Rhys Allan, Juliana Babu, Michael Bale, Meriem Belabed, Christophe Benoist, Michelle Bessiake, Maria Brbic, Brian D. Brown, Jason Buenrostro, Odhran Casey, Marco Colonna, Myriam Croze, Fabiana Duarte, Daniel Dwyer, Andrew Earl, Jeff Ericson, Shawn Fan, Kaili Fan, Enxhi Ferraj, Michela Frascoli, Antoine Freuchet, Giovanni Galleti, Anna Globig, Ananda Goldrath, Alessandra Gurtner, Pauline Hamon, Jichang Han, Samarth Hedge, Max Heeg, Molly Henderson, Geon Ho Bae, David Hoytema van Konijnenburg, Ruaidhri Jackson, Tim Johanson, Steve Josefowicz, Harry Kane, Joonsoo Kang, Mythili Ketavarapu, Catherine Laplace, Jessica Le Berichel, Alexander Liu, Vida Luna, Ian Magill, Diane Mathis, Raphael Matthiuz, Miriam Merad, Chang Moon, Alexander Monell, Sara Mostafavi, Hadas Ner-Gaon, Trung Nguyen, Junli Nie, Rachel Niec, Peter Nigrovic, Stephen Nutt, Adriana Ortiz-Lopez, Mark Owyong, Hadas Pahima, Siba Panigrahi, Matthew Park, Quan Phan, Gwendalyn Randolph, Miguel Reina-Campos, Alexander Sasse, Maximilian Schaefer, Tal Shay, Rojesh Shrestha, Justin Shyer, Sangwan Sim, Bhavya Singh, Joseph Sun, Kennidy Takehara, Julie Tellier, Alex Tepper, Xinming Tu, Olivia Venezia, Amy Wagers, Tianze Wang, Sunny Wu, Tong Wu, Ethan Xu, Liang Yang, David Zemmour, and Leon Zhou.
- Award Id(s): AI072073
Juliana J. Lee, Liang Yang, Jonathan J. Kotzin, Dughan Ahimovic, Michael J. Bale, Peter A. Nigrovic, Steven Z. Josefowicz, Diane Mathis, Christophe Benoist, Immunological Genome Project Consortium; Early transcriptional effects of inflammatory cytokines reveal highly redundant cytokine networks. J Exp Med 7 April 2025; 222 (4): e20241207. doi: https://doi.org/10.1084/jem.20241207
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