Early transcriptional effects of inflammatory cytokines reveal highly redundant cytokine networks
Juliana J. Lee, Liang Yang, Jonathan J. Kotzin, Dughan Ahimovic, Michael J. Bale, Peter A. Nigrović, Steven Z. Josefowicz, Diane Mathis, Christophe Benoıst, Dughan Ahimovic, Rhys S. Allan, Juliana Babu, Michael J. Bale, Meriem Belabed, Christophe Benoıst, Michelle Bessiake, Maria Brbić, Brian D. Brown, Jason D. Buenrostro, Odhran Casey, Marco Colonna, Myriam Croze, Fabiana M. Duarte, Daniel F. Dwyer, Andrew Earl, Jeff Ericson, Shawn Fan, Kaili Fan, Enxhi Ferraj, Michela Frascoli, Antoine Freuchet, Giovanni Galleti, Anna-Maria Globig, Ananda W. Goldrath, Alessandra Gurtner, Pauline Hamon, Jichang Han, Samarth Hedge, Maximilian Heeg, Mark Henderson, Geon Ho Bae, David Hoytema van Konijnenburg, Ruaidhrí Jackson, Tim Johanson, Steve Josefowicz, Harry Kane, Joonsoo Kang, Mythili Ketavarapu, Catherine Laplace, Jessica Le Bérichel, Alexander Liu, Vida Luna, Ian Magill, Diane Mathis, Raphael Matthiuz, M.S. Merad, Chang Moon, Alexander Monell, Sara Mostafavi, Hadas Ner‐Gaon, Trung C. Nguyen, Junli Nie, Rachel Niec, Peter A. Nigrović, Stephen L. Nutt, Adriana Ortiz-Lopez, Mark Owyong, Hadas Pahima, S.K. Panigrahi, Matthew Park, Quan M Phan, Gwendalyn J. Randolph, Miguel Reina‐Campos, Alexander Sasse, Maximilian Schaefer, Tal Shay, Rojesh Shrestha, Justin A. Shyer, S.I. Sim, Bhavya Singh, Joseph C. Sun, Kennidy K. Takehara, Julie Tellier, Alex Tepper, Xinming Tu, Olivia Venezia, Amy J. Wagers, Tianze Wang, Sunny Z. Wu, Tong Wu, Ethan Xu, Liang Yang, David Zemmour, Leon Zhou
Abstract
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.