IL-17F mirrors IL-17A in dermal fibroblasts and synergizes with TNF to drive inflammation in Th17 inflammatory skin diseases.

T helper 17 (Th17)-mediated skin diseases, such as psoriasis and hidradenitis suppurativa, are driven by a dysregulated cytokine network where the specific contribution of Interleukin (IL)-17F has historically been underestimated due to its lower intrinsic potency compared to IL-17 A. To elucidate the role of IL-17F in the dermal compartment, we performed bulk RNA sequencing on primary human dermal fibroblasts stimulated with recombinant IL-17 A or IL-17F, either alone or in combination with Tumor Necrosis Factor (TNF). While single stimulation confirmed the superior potency of IL-17 A, the addition of TNF completely abolished this hierarchy. Transcriptional profiling demonstrated that TNF synergizes potently with IL-17F, amplifying its inflammatory output to levels almost indistinguishable from the IL-17 A and TNF combination. This synergistic interplay drove a robust upregulation of pathogenic mediators, including neutrophil-attracting chemokines (CXCL1, CXCL8) and tissue-destructive enzymes (MMP1). These findings challenge the paradigm of IL-17F as a redundant homolog, demonstrating that within a TNF-rich pro-inflammatory environment, IL-17F overcomes its limited basal potency to mirror the inflammatory drive of IL-17 A functionally. This mechanism provides a biological rationale for the superior clinical efficacy observed with dual IL-17 A/F inhibition in chronic inflammatory skin diseases.