IL11 stimulates IL33 expression and proinflammatory fibroblast activation

Interleukin 11 (IL11) is upregulated in inflammatory conditions where it is believed to have anti-inflammatory activity. However, recent studies suggest instead that IL11 may promote inflammation, via the stroma. Here, we assessed whether IL11 is pro- or anti-inflammatory in fibroblasts. Primary cultures of human kidney, lung or skin fibroblasts were stimulated with IL11 that resulted in transient STAT3 phosphorylation and bi-modal ERK activation. RNA sequencing over a time course of IL11 stimulation revealed a robust short-lived transcriptional response, which was enriched for gene set hallmarks of inflammation and characterized by upregulation of SERPINB2, TNFRSF18, IL33, CCL20, IL1RL1, CXCL3/5/8, ICAM1 and IL11 itself. IL33 was the most upregulated signaling factor (38-fold, P=9.8×10−5) and IL1RL1 , its cognate receptor, was similarly increased (18-fold, P=1.1×10−34). In proteomic studies, IL11 triggered a proinflammatory secretome with notable upregulation of IL8, IL6, MCP1, CCL20 and CXCL1/5/6, which are important chemotaxins for neutrophils, monocytes and lymphocytes. IL11 induced IL33 expression across fibroblast types and inhibition of STAT3, but not MEK/ERK, prevented this. These data establish IL11 as pro-inflammatory with specific importance for priming the IL33 alarmin response in inflammatory fibroblasts. ### Competing Interest Statement S.A.C is co-inventor of the patent applications WO/2018/109174 (IL11 ANTIBODIES), WO/2018/109170 (IL11RA ANTIBODIES), co-founder and shareholder of Enleofen Bio PTE LTD.