Uterocalin (Lcn2; also called 24p3, SIP24, or siderocalin and abbreviated as Utc) is an acute phase protein, for which the physiological function remains to be determined. Basal Utc expression is highest in the uterus, mammary gland and lung, which are three tissues with direct exposure to the diverse bacterial flora of the external environment. The demonstrated ability to bind siderophores is one means by which Utc can provide protection against pathogenic bacteria. However, its specificity for siderophores limits the ability of Utc to ward off pathogens. Epithelial tissues that interact with the external environment are exposed to many different nonpathogenic resident bacteria to which the tissue normally does not mount an inflammatory response. We postulate that Utc might limit inflammation by suppressing cytokine expression in response to bacterial products such as LPS. To test this hypothesis, we studied the effect of LPS, delivered by intranasal administration, in Lcn2-deficient mice (Lcn2-/-) and their wild type littermates. Utc is highly expressed in the lungs of normal mice at 4 h and 48 h after LPS intranasal challenge. By multiplexed and real-time RT-PCR we found that 6 h after intranasal administration of LPS (0.4 to 4 mg/kg), the expression of TNF-alpha, IL-1beta and IL-6 was increased in Lcn2-/- compared with their wild type littermates. H & E immunohistochemical staining of the lung and liver showed that the higher dose of LPS (4 mg/kg) caused the entry of some neutrophils into the lungs of Lcn2-/- animals and their wild type littermates. No neutrophils were observed in the lung and liver from mice treated at the lower doses. The reaction of older Lcn2-/- mice (11 or 14 weeks old) in response to the LPS intranasal administration was more dramatic compared with younger mice (7 or 8 weeks old). In summary, our results indicate that Lcn2 may play an anti-inflammatory role in the lung and liver and provide feedback regulation of the acute phase response by suppressing pro-inflammatory cytokine expression.