* CL and RV contributed equally to this work.
Dear EditorWith great interest we read the recent publication from Vinter and colleagues describing the role of TNFα in the Aldara model 1 . Through the use of scoring skin inflammation, RT-PCR, and histology, they showed that TNFα-deficient mice showed less erythema, scaling, epidermal hyperplasia, Ki67, CD3 + T cells staining and splenomegaly. The authors continued by quantifying several mediating cytokines, such as IL-17A, IL-22, IL-12p40, and IL-23p19; which were significantly reduced in TNFα-knockouts. They also quantified interferon regulatory factor (IRF) -7, which on day 1 was clearly elevated in response to Aldara. Similar dynamics and levels were observed in TNFα-knockouts. Therefore, the authors conclude that TNFα does not affect the early type I interferon response. However, we believe this statement is not sufficiently supported by their study and kindly refer the authors to our previous study with TNFR1-knockout mice, which showed a sustained type I interferon response within hours after application 2 . First, we found that IFNα levels in the skin decreased in response to repetitive Aldara treatment. In contrast, TNFR1-knockouts showed steady levels instead. Measurement of IFNα and IFNβ in wild type serum revealed a peak at 3 hours after Aldara, whereas the levels kept increasing in the absence of TNFR1. A similar trend was found in the expression levels of Cxcl10, Ifit2, and Usp18; interferon-responsive genes. We attribute these results to the TNF/TNFR1 pathway negatively regulating type I interferon production in response to Aldara.Since TNFα may act through two different receptors, TNFR1 and TNFR2, it is difficult to interpret results obtained with TNFα-knockout mice only. Yet, similar to the findings of Vinter and coworkers, TNFR1-deficient mice in our study showed reduced IL-12p40 and S100A8 levels.