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The precise context in which the innate immune system is activated plays a pivotal role in the subsequent instruction of CD4+ T helper (Th) cell responses. Th1 responses are downregulated when antigen is encountered in the presence of antigen-IgG immune complexes. To assess if Th17 responses to antigen are subject to similar influences in the presence of immune complexes we utilized an inflammatory airway disease model in which immunization of mice with Complete Freund’s Adjuvant (CFA) and ovalbumin (Ova) induces a powerful Ova-specific Th1 and Th17 response. Here we show that modification of that immunization with CFA to include IgG-Ova immune complexes results in the suppression of CFA-induced Th17 responses and a concurrent enhancement of Ova-specific Th2 responses. Furthermore, we show the mechanism by which these immune complexes suppress Th17 responses is through the enhancement of IL-10 production. In addition, the generation of Th17 responses following immunization with CFA and Ova were dependent on IL-1α but independent of NLRP3 inflammasome activation. Together these data represent a novel mechanism by which the generation of Th17 responses is regulated. [ABSTRACT FROM AUTHOR]

SOCS-1 is a critical regulator of multiple signaling pathways, including those activated by cytokines that regulate Ig H chain class switching to IgE. Analysis of mice with mutations in the SOCS-1 gene demonstrated that tgE levels increase with loss of SOCS-1 alleles. This suggested that overall SOCS-1 acts as an inhibitor of IgE expression in vivo. A genetic association study was performed in 474 children enrolled in the Tucson Children's Respiratory Study to determine if genetic variation in the SOCS-1 locus correlates with altered levels of IgE. Carriers of the C-allele for a novel, 3' genomic single nucleotide polymorphism (SNP) in the SOCS-1 gene (SOCS1+1125G > C; rs33932899) were found to have significantly lower levels of serum IgE compared with those of homozygotes for the G-allele. Analysis demonstrated that the SOCS1+1125G > C SNP was in complete linkage disequi- librium with an SN? at position SOCS-1 -820G > T (rs33977706) of the SOCS-1 promoter. Carriers of the T-allele at the SOCS1- 820G > T were also found to be associated with the decreased IgE. The promoter SNP increased transcriptional activity of the SOCS-1 promoter in reporter assays and human B cells. Consistent with this observation, the presence of this polymorphism within the promoter abolished binding of yin yang-1, which is identified as a negative regulator of SOCS-1 transcriptional activity. These data suggest that genetic variation in the SOCS-1 promoter may affect IgE production. [ABSTRACT FROM AUTHOR]

Summary: The NLRP3 inflammasome is activated in response to a variety of signals that are indicative of damage to the host including tissue damage, metabolic stress, and infection. Upon activation, the NLRP3 inflammasome serves as a platform for activation of the cysteine protease caspase-1, which leads to the processing and secretion of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. Dysregulated NLRP3 inflammasome activation is associated with both heritable and acquired inflammatory diseases. Here, we review new insights into the mechanism of NLRP3 inflammasome activation and its role in disease pathogenesis. [ABSTRACT FROM AUTHOR]

Type 2 T helper (TH2) cells are critical for the development of allergic immune responses; however, the molecular mechanism controlling their effector function is still largely unclear. Here, we report that the transcription factor NFIL3/E4BP4 regulates cytokine production and effector function by TH2 cells. NFIL3 is highly expressed in TH2 cells but much less in TH1 cells. Production of interleukin (IL)-13 and IL-5 is significantly increased in Nfil3−/− TH2 cells and is decreased by expression of NFIL3 in wild-type TH2 cells. NFIL3 directly binds to and negatively regulates the Il13 gene. In contrast, IL-4 production is decreased in Nfil3−/− TH2 cells. Increased IL-13 and IL-5 together with decreased IL-4 production by antigen-stimulated splenocytes from the immunized Nfil3−/− mice was also observed. The ability of NFIL3 to alter TH2 cytokine production is a T-cell intrinsic effect. Taken together, these data indicate that NFIL3 is a key regulator of TH2 responses. [ABSTRACT FROM AUTHOR]

Cytokines are powerful mediators of the immune response that, following initial release by components of the innate system, drive effector functions as well as stimulate the additional arms of the response. Their individual functions are diverse, with stimulatory and inhibitory actions, with the resultant systemic immune response a summation of these actions. The frequently opposing effects of cytokines determine that the blockade of one results in the functional augmentation of the other. Thus, the differential regulation of cytokines profoundly influences the character of the immune response. The suppressor of cytokine signaling proteins are a family of molecules pivotal to this critical regulation. In this review, we will discuss their structural components and functions and our understanding of their impact on the systemic immune response. [ABSTRACT FROM AUTHOR]

The NLR (nucleotide-binding domain leucine-rich repeat containing) family of intracellular sensors is a crucial component of the innate immune system. A number of NLR family members can form multiprotein complexes, called inflammasomes, and are capable of activating the cysteine protease caspase-1 in response to a wide range of stimuli including both microbial and self-molecules. Caspase-1 activation leads to processing and secretion of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18, which play crucial roles in host defense to infectious insults. Dysregulation of the inflammasome has also been linked to a number of autoinflammatory and autoimmune disorders. Recent advances in the inflammasome field will be discussed in this review. [Copyright &y& Elsevier]