TY - JOUR
T1 - RNA-seq analysis of IL-1B and IL-36 responses in epidermal keratinocytes identifies a shared MyD88-dependent gene signature
AU - Swindell, William R.
AU - Beamer, Maria A.
AU - Sarkar, Mrinal K.
AU - Loftus, Shannon
AU - Fullmer, Joseph
AU - Xing, Xianying
AU - Ward, Nicole L.
AU - Tsoi, Lam C.
AU - Kahlenberg, Michelle J.
AU - Liang, Yun
AU - Gudjonsson, Johann E.
N1 - Publisher Copyright:
© 2018 Swindell, Beamer, Sarkar, Loftus, Fullmer, Xing, Ward, Tsoi, Kahlenberg, Liang and Gudjonsson.
PY - 2018/1/29
Y1 - 2018/1/29
N2 - IL-36 cytokines have recently emerged as mediators of inflammation in autoimmune conditions including psoriasis vulgaris (PsV) and generalized pustular psoriasis (GPP). This study used RNA-seq to profile the transcriptome of primary epidermal keratinocytes (KCs) treated with IL-1B, IL-36A, IL-36B, or IL-36G. We identified some early IL-1B-specific responses (8 h posttreatment), but nearly all late IL-1B responses were replicated by IL-36 cytokines (24 h posttreatment). Type I and II interferon genes exhibited time-dependent response patterns, with early induction (8 h) followed by no response or repression (24 h). Altogether, we identified 225 differentially expressed genes (DEGs) with shared responses to all 4 cytokines at both time points (8 and 24 h). These involved upregulation of ligands (IL1A, IL1B, and IL36G) and activating proteases (CTSS) but also upregulation of inhibitors such as IL1RN and IL36RN. Shared IL-1B/IL-36 DEGs overlapped significantly with genes altered in PsV and GPP skin lesions, as well as genes near GWAS loci linked to autoimmune and autoinflammatory diseases (e.g., PsV, psoriatic arthritis, inflammatory bowel disease, and primary biliary cholangitis). Inactivation of MyD88 adapter protein using CRISPR/Cas9 completely abolished expression responses of such DEGs to IL-1B and IL-36G stimulation. These results provide a global view of IL-1B and IL-36 expression responses in epidermal KCs with fine-scale characterization of time-dependent and cytokine-specific response patterns. Our findings support an important role for IL-1B and IL-36 in autoimmune or autoinflammatory conditions and show that MyD88 adaptor protein mediates shared IL-1B/IL-36 responses.
AB - IL-36 cytokines have recently emerged as mediators of inflammation in autoimmune conditions including psoriasis vulgaris (PsV) and generalized pustular psoriasis (GPP). This study used RNA-seq to profile the transcriptome of primary epidermal keratinocytes (KCs) treated with IL-1B, IL-36A, IL-36B, or IL-36G. We identified some early IL-1B-specific responses (8 h posttreatment), but nearly all late IL-1B responses were replicated by IL-36 cytokines (24 h posttreatment). Type I and II interferon genes exhibited time-dependent response patterns, with early induction (8 h) followed by no response or repression (24 h). Altogether, we identified 225 differentially expressed genes (DEGs) with shared responses to all 4 cytokines at both time points (8 and 24 h). These involved upregulation of ligands (IL1A, IL1B, and IL36G) and activating proteases (CTSS) but also upregulation of inhibitors such as IL1RN and IL36RN. Shared IL-1B/IL-36 DEGs overlapped significantly with genes altered in PsV and GPP skin lesions, as well as genes near GWAS loci linked to autoimmune and autoinflammatory diseases (e.g., PsV, psoriatic arthritis, inflammatory bowel disease, and primary biliary cholangitis). Inactivation of MyD88 adapter protein using CRISPR/Cas9 completely abolished expression responses of such DEGs to IL-1B and IL-36G stimulation. These results provide a global view of IL-1B and IL-36 expression responses in epidermal KCs with fine-scale characterization of time-dependent and cytokine-specific response patterns. Our findings support an important role for IL-1B and IL-36 in autoimmune or autoinflammatory conditions and show that MyD88 adaptor protein mediates shared IL-1B/IL-36 responses.
KW - ETS1
KW - Epidermis
KW - IL-1
KW - Inflammatory bowel disease
KW - Keratinocytes
KW - NF-kappaB
KW - RNA-seq
UR - http://www.scopus.com/inward/record.url?scp=85041237499&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041237499&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2018.00080
DO - 10.3389/fimmu.2018.00080
M3 - Article
C2 - 29434599
AN - SCOPUS:85041237499
SN - 1664-3224
VL - 9
JO - Frontiers in immunology
JF - Frontiers in immunology
IS - JAN
M1 - 80
ER -