Type I Interferon Inhibits Interleukin-1 Production and Inflammasome Activation

Abstract

Type I interferon (IFN) is a common therapy for autoimmune and inflammatory disorders, yet the mechanisms of action are largely unknown. Here we showed that type I IFN inhibited interleukin-1 (IL-1) production through two distinct mechanisms. Type I IFN signaling, via the STAT1 transcription factor, repressed the activity of the NLRP1 and NLRP3 inflammasomes, thereby suppressing caspase-1-dependent IL-1β maturation. In addition, type I IFN induced IL-10 in a STAT1-dependent manner; autocrine IL-10 then signaled via STAT3 to reduce the abundance of pro-IL-1α and pro-IL-1β. In vivo, poly(I:C)-induced type I IFN diminished IL-1β production in response to alum and Candida albicans, thus increasing susceptibility to this fungal pathogen. Importantly, monocytes from multiple sclerosis patients undergoing IFN-β treatment produced substantially less IL-1β than monocytes derived from healthy donors. Our findings may thus explain the effectiveness of type I IFN in the treatment of inflammatory diseases but also the observed "weakening" of the immune system after viral infection.

Cellular and molecular mechanisms in liver fibrogenesis

“…In order to obtain full activation (that is, to obtain the effective synthesis and release of active IL-1β and IL-18) the inflammasome typically requires two distinct signals: i) a first priming signal usually triggered either by PAMPs interacting with PRRs as well as by inflammatory citokines (TNF or IL-1) interacting with the related receptor; the first signal is designed to activate transcription of the genes encoding pro-IL-1β, pro-IL-18 and NLRP3 [110]; ii) the second signal can be provided by various inflammasome ligands (including PAMPs) through involvement/activation of cytosolic NLR (NOD-like receptor) proteins, particularly NLRP3, which in turn leads to activation of caspase-1 and cleavage of pro-IL-1β and pro-IL-18 into the active forms [111]; the second signal can be reinforced by ROS generated after exposure to PAMPs and DAMPs. Inflammasome can be modulated by at least two further events: a) it has been reported that a cross-talk exists between inflammasome and autophagy; in particular, autophagic suppression of ROS generation (i.e., by sequestering in autophagosomes defective mitochondria which may represent a source of ROS) indirectly inhibits inflammasome activity [112]; b) inflammasome activity is inhibited by either cell-cell interactions or secreted factors (for example IFN) involving lymphocytes of adaptive immunity, particularly CD4+ effector and memory T cells [113].…”

Caspases as the Key Effectors of Inflammatory Responses Against Bacterial Infection

“…In addition to the activation mechanisms triggered by cellular stresses, caspase-1-NLRP3 inflammasomes have been shown to be regulated by unique mechanisms (Tsuchiya and Hara 2014). Type I IFNs suppress the activation of the NLRP3 inflammasome and mature IL-1b production in a STAT1/3-dependent manner (Guarda et al 2011). In addition, nitrogen oxide (NO) negatively regulated NLRP3 inflammasome activation through S-nitrosylation (Hernandez-Cuellar et al 2012).…”

“…The production of IL-1b/IL-18 is regulated by Type I IFNs (Guarda et al 2011;Rathinam et al 2012). In addition, L. monocytogenes infections induce the expression of Type I IFNs including IFN-b (Reimer et al 2007;Reutterer et al 2008;Yamamoto et al 2012).…”

Oral Palmitoylethanolamide Treatment Is Associated with Reduced Cutaneous Adverse Effects of Interferon-β1a and Circulating Proinflammatory Cytokines in Relapsing–Remitting Multiple Sclerosis

“…Consistent with the reduced IL-17 serum levels in the um-PEA-treated group, we also found reduced TNF-α serum levels. Importantly, this effect is obtained under IFN-β1a treatment, which per se reduces the proinflammatory cytokine serum levels in MS [52][53][54]. Inflammatory mediators, such as IFN-γ and TNF-α are known key contributors to the induction and maintenance of autoimmune diseases [55][56][57][58].…”