Severe infections with Gram-negative bacteria can lead to systemic inflammation, endotoxic shock and, potentially, death. The Gram-negative cell wall component lipopolysaccharide (LPS) is a potent inducer of inflammatory cytokines that contribute significantly to the pathology of Gram-negative sepsis. Mechanisms that drive and restrain LPS-induced inflammatory cytokine responses are therefore of specific interest. Wnt proteins are phylogenetically conserved regulators of cell differentiation during embryonic development and in the adult organism. Their recent association with chronic inflammation and bacterial infections, including severe Gram-negative sepsis, in patients and animal models has indicated novel immune-related functions of Wnt proteins. Both, pro- and anti-inflammatory properties of Wnt proteins have been described. However, the sources and targets of Wnt proteins as well as their functions in complex immune settings in vivo are largely unknown. Using a mouse model of LPS-induced endotoxemia, we observed differential Wnt expression in the spleen and liver upon LPS-challenge. While macrophages and dendritic cells have previously been described as sources of Wnt proteins during infection, we further identified cell-type specific LPS-responsive patterns of Wnt expression not only by myeloid cells but also T and B lymphocytes. Pharmacological targeting of a central enzyme essential for the production of functional Wnt proteins lead to reduced mRNA expression of inflammatory cytokines in the spleen and diminished serum levels of a subset of pro-inflammatory mediators. Our findings suggest that Wnt protein production enhances LPS-induced cytokine responses in vivo, indicating an overall pro-inflammatory contribution of Wnt proteins during endotoxemia. Thus, detailed understanding of the functions of Wnt proteins as regulators of inflammatory responses might identify novel indicators of inflammation and potential therapeutic strategies in severe infections.