IL-17A was cloned more than 10 years ago and six IL-17 family members (IL-17A-F) have subsequently been described. IL-17A is largely produced by activated memory T lymphocytes but stimulates innate ...immunity and host defense. IL-17A and IL-17F both mobilize neutrophils partly through granulopoeisis and CXC chemokine induction, as well as increased survival locally. IL-17A and IL-17F production by T lymphocytes is regulated by IL-23 independent of T cell receptor activation. Increasing evidence shows that IL-17 family members play an active role in inflammatory diseases, autoimmune diseases, and cancer. This places IL-17 family members and their receptors as potential targets for future pharmacotherapy.
Interleukin‐22 (IL‐22), a recently identified member of the IL‐10 family of cytokines that is produced by Th17 and natural killer cells, plays an important role in controlling bacterial infection, ...homeostasis, and tissue repair. Here, we tested the effect of IL‐22 on alcohol‐induced liver injury in a murine model of chronic‐binge ethanol feeding. Feeding male C57BL/6 mice with a Lieber‐DeCarli diet containing 5% ethanol for 10 days, followed by a single dose of ethanol (5 g/kg body weight) by gavage, induces significant fatty liver and liver injury with peak serum levels of approximately 250 IU/L alanine aminotransferase and 420 IU/L aspartate aminotransferase 9 hours after gavage. Moreover, chronic‐binge ethanol administration increases expression of hepatic and serum inflammatory cytokines and hepatic oxidative stress. Using this model, we demonstrate that treatment with IL‐22 recombinant protein activates hepatic signal transducer and activator of transcription 3 (STAT3) and ameliorates alcoholic fatty liver, liver injury, and hepatic oxidative stress. Administration with IL‐22 adenovirus also prevents alcohol‐induced steatosis and liver injury. Deletion of STAT3 in hepatocytes abolishes the hepatoprotection provided by IL‐22 in alcoholic liver injury. In addition, IL‐22 treatment down‐regulates the hepatic expression of fatty acid transport protein, but up‐regulates several antioxidant, antiapoptotic, and antimicrobial genes. Finally, expression of IL‐22 receptor 1 is up‐regulated whereas IL‐22 is undetectable in the livers from mice with chronic‐binge ethanol feeding or patients with alcoholic hepatitis. Conclusion: Chronic‐binge ethanol feeding may be a useful model to study the early stages of alcoholic liver injury. IL‐22 treatment could be a potential therapeutic option to ameliorate alcoholic liver disease, due to its antioxidant, antiapoptotic, antisteatotic, proliferative, and antimicrobial effects with the added benefit of potentially few side effects. HEPATOLOGY 2010
Highlights • Th17 responses show protection against both bacterial and fungal pathogens. • Mucosal and systemic vaccines can elicit protective Th17 responses. • Th17 responses can mediate serotype ...immunity against clades of organisms.
Highlights ► Pattern recognition receptors respond to a wide variety of bacterial pathogens in the lung. ► IL-23 stimulates innate production of IL-17 and IL-22 which increase lung defenses. ► CD4+ T ...cell subtypes play a critical role in orchestrating lung immunity. ► Lung epithelia can modulate B cell maturation through BAFF and APRIL.
Fungal infections are of increasing incidence and importance in immunocompromised and immunocompetent patients. Timely diagnosis relies on appropriate use of laboratory testing in susceptible ...patients.
The relevant literature related to diagnosis of invasive pulmonary aspergillosis, invasive candidiasis, and the common endemic mycoses was systematically reviewed. Meta-analysis was performed when appropriate. Recommendations were developed using the Grading of Recommendations Assessment, Development, and Evaluation approach.
This guideline includes specific recommendations on the use of galactomannan testing in serum and BAL and for the diagnosis of invasive pulmonary aspergillosis, the role of PCR in the diagnosis of invasive pulmonary aspergillosis, the role of β-d-glucan assays in the diagnosis of invasive candidiasis, and the application of serology and antigen testing in the diagnosis of the endemic mycoses.
Rapid, accurate diagnosis of fungal infections relies on appropriate application of laboratory testing, including antigen testing, serological testing, and PCR-based assays.
Abstract The T helper type 17 (Th17) lineage of CD4+ T-cells produce several effector molecules including IL-17A, IL-17F, IL-21, and IL-22. In addition to CD4+, αβ T-cells, these cytokines can be ...produced by natural killer and γδ T-cells. These effector cytokines can be produced rapidly upon infection at mucosal sites and evidence to date strongly implicates that this arm of the immune system plays a critical role in mucosal immunity to many extracellular pathogens. Moreover these cytokines can also coordinate adaptive immunity to some intracellular pathogens. In this review, we will highlight recent progress in our understanding of these cytokines, and mechanisms of their effector function in the mucosa.
Interleukin-17 (IL-17) induces pathology in autoimmunity and infections; therefore, constraint of this pathway is an essential component of its regulation. We demonstrate that the signaling ...intermediate MCPIP1 (also termed Regnase-1, encoded by Zc3h12a) is a feedback inhibitor of IL-17 receptor signal transduction. MCPIP1 knockdown enhanced IL-17-mediated signaling, requiring MCPIP1’s endoribonuclease but not deubiquitinase domain. MCPIP1 haploinsufficient mice showed enhanced resistance to disseminated Candida albicans infection, which was reversed in an Il17ra−/− background. Conversely, IL-17-dependent pathology in Zc3h12a+/− mice was exacerbated in both EAE and pulmonary inflammation. MCPIP1 degraded Il6 mRNA directly but only modestly downregulated the IL-6 promoter. However, MCPIP1 strongly inhibited the Lcn2 promoter by regulating the mRNA stability of Nfkbiz, encoding the IκBζ transcription factor. Unexpectedly, MCPIP1 degraded Il17ra and Il17rc mRNA, independently of the 3′ UTR. The cumulative impact of MCPIP1 on IL-6, IκBζ, and possibly IL-17R subunits results in a biologically relevant inhibition of IL-17 signaling.
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•MCPIP1 (Regnase-1) is a feedback inhibitor of IL-17 signal transduction•MCPIP1 deficiency enhances immunity to fungi but exacerbates pathology in EAE•MCPIP1 impairs activation of certain IL-17 target promoters by degrading IκBζ mRNA•MCPIP1 degrades transcripts encoding IL-17R subunits independently of the 3′ UTR
Interleukin-17 (IL-17) induces pathology in autoimmunity and infections and therefore its activity must be tightly regulated. Gaffen and colleagues report that the endoribonuclease MCPIP1 degrades IL-17-induced transcripts, including Il6 and Nfkbiz (Iκβζ), to negatively regulate IL-17 receptor signaling both in fungal immunity and experimental autoimmune encephalomyelitis.
Iwanaga and Kolls discuss the study by Schupp et al who performed a single-cell RNAseq analyses in sputum between nine cystic fibrosis (CF) subjects and five healthy control subjects. The authors ...found a cluster of recruited lung mononuclear phagocytes in CF sputum and identified three different archetypes of monocytes: activated monocytes, monocyte-derived macrophages, and heat shock-activated monocytes. Also, the authors observed a complex population of polymorphonuclear neutrophils (PMN) based on the inflammatory genes and genes involved in PMN maturation, which was quite distinct from healthy control subjects.
Importantly, they chose a 14-day time point after Pneumocystis inoculation, as this time point coincided with the induction of adaptive immune responses that are just initializing clearance, yet ...fungal burdens are quite similar between control and steroid-treated animals. ...differences in gene expression largely reflect defects in host immunity and are not skewed by differences in fungal burdens between the groups. A similar defect in T cell priming occurs in mice treated with CD20 (2) or in mice lacking secreted IgM (6). ...in primary infection, B cells appear to be critical to elicit T cell immunity to this infection.
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