Absence of IL-1 signaling and reduced inflammatory response in IL-1 type I receptor-deficient mice.

Abstract

IL-1alpha and IL-1beta are potent inflammatory cytokines that contribute to a number of normal physiologic processes and to the development of a number of inflammatory diseases. Two IL-1R, the type I and type II receptors, have been identified. This work describes the derivation and characterization of mice deficient in expression of the type I IL-1R (IL-1RI). IL-1RI-deficient mice were viable and fertile, but failed to respond to IL-1 in a variety of assays, including IL-1-induced IL-6 and E-selectin expression and IL-1-induced fever. Similar to IL-1beta-deficient mice, IL-1RI-deficient mice had a reduced acute phase response to turpentine. In contrast, IL-1RI-deficient mice had a reduced delayed-type hypersensitivity response and were highly susceptible to infection by Listeria monocytogenes. These data demonstrate that the IL-1RI is essential for all IL-1-mediated signaling events examined, and that both IL-1alpha and IL-1beta are critical to the animals' response to injury and infection. These data also demonstrate that IL-1 function is not required for normal development or homeostasis.

Inflammasomes: a novel therapeutic target in pulmonary hypertension?

“…Additionally, inflammasome generated caspase-1 promotes a highly inflammatory type of cell death known as pyroptosis (Maltez et al, 2015). The IL-1 family of cytokines are 'early response' mediators of immunity and promote the release of a number of secondary cytokines which lie further downstream in the inflammasome activation cascade (Labow et al, 1997;Dinarello, 2002;Cahill and Rogers, 2008;Mills et al, 2013). These include IL-6, which is released from macrophages and T-cells in response to IL-1β stimulation (Cahill and Rogers, 2008), as well as IL-2 and IL-12 which are produced downstream of IL-18 (Dinarello, 2002).…”

“…The early response IL-1 family of cytokines released by inflammasomes promote the release of secondary cytokines lying further downstream (Labow et al, 1997;Dinarello, 2002;Cahill and Rogers, 2008;Mills et al, 2013); akin to the primary cytokines, most of these have also been implicated in PH. Firstly, IL-1β stimulation promotes IL-6 release from macrophages and T-cells (Cahill and Rogers, 2008), and secondly, IL-2 and IL-12 are produced downstream of IL-18 (Dinarello, 2002).…”

IL‐1β and IL‐18: inflammatory markers or mediators of hypertension?

“…This means that they are released in the earliest stage of an immune response and act as a trigger for a subsequent cascade of proinflammatory cytokines. IL-1β stimulates the release of IL-6 and IL-17a, while IL-18 promotes the production of IFN-γ, IL-2 and IL-12 (Labow et al, 1997;Dinarello, 2002;Cahill and Rogers, 2008;Mills et al, 2013). These downstream cytokines are associated with highly proinflammatory T-helper 1 (Th1)-and T-helper 17 (Th17)-type immune responses and there is evidence to suggest that Th1 and Th17 cells play a major role in hypertension (Shao et al, 2003;Platten et al, 2009;Madhur et al, 2010).…”

The inflammatory microenvironment of the lung at the time of infection governs innate control of SARS-CoV-2 replication

“…C57BL/6 mice (Taconic farms), C57BL/6 mice expressing a Foxp3 -GFP reporter (C57BL/6- Foxp3 tm1Kuch ) 169 or the Thy1.1 allele (B6.PL-Thy1 a /CyJ) were used as wild type C57BL/6 controls in experiments. Foxp3 -GFP mice, Thy1.1 mice, Ifnar1 −/− mice (B6.129S2- Ifnar1 tm1Agt backcrossed to B6 for 12 generations) 170 , Tlr3 −/− mice (B6;129S1- Tlr3 tm1Flv /J backcrossed to B6 for 11 generations) 171 , Ifih1 −/− mice (B6.Cg- Ifih1 tm1.1Cln /J) 172 , Ccr2 −/− mice (B6.129S4- Ccr2 tm1Ifc /J) 173 , Nlrp3 −/− mice (B6N.129- Nlrp3 tm2Hhf /J) 174 , Tnfrsf1a −/− mice (C57BL/6- Tnfrsf1a tm1Imx /J) 175 , Ccr5 −/− mice (B6.129P2- Ccr5 tm1Kuz /J) 176 , Casp1,11 −/− mice (B6N.129S2- Casp1 tm1Flv /J) 177 , Il1r1 −/− mice (B6;129S1- Il1r1 tm1Rom l /J backcrossed to B6 for 12 generations) 178 were all obtained through a supply breeding contract between NIAID and Taconic Farms. Zbp1 −/− mice were made in-house by CRISPR/Cas9 genetic targeting as detailed below.…”