Interleukin-22: Immunobiology and Pathology Dudakov, Jarrod A; Hanash, Alan M; van den Brink, Marcel R.M
Annual review of immunology,
03/2015, Volume:
33, Issue:
1
Journal Article
Peer reviewed
Open access
Interleukin-22 (IL-22) is a recently described IL-10 family cytokine that is produced by T helper (Th) 17 cells, γδ T cells, NKT cells, and newly described innate lymphoid cells (ILCs). Knowledge of ...IL-22 biology has evolved rapidly since its discovery in 2000, and a role for IL-22 has been identified in numerous tissues, including the intestines, lung, liver, kidney, thymus, pancreas, and skin. IL-22 primarily targets nonhematopoietic epithelial and stromal cells, where it can promote proliferation and play a role in tissue regeneration. In addition, IL-22 regulates host defense at barrier surfaces. However, IL-22 has also been linked to several conditions involving inflammatory tissue pathology. In this review, we assess the current understanding of this cytokine, including its physiologic and pathologic effects on epithelial cell function.
Transforming growth factor-beta (TGFβ) proteins induce an epithelial-mesenchymal transition (EMT) programme that is associated with increased invasive and drug-resistant phenotype of carcinoma cells. ...In addition to the canonical pathway involving SMAD proteins, the mitogen-activated kinase (MAPK) pathway via extracellular signal-regulated kinases ½ (ERK1/2) is also involved in promoting and maintaining a mesenchymal phenotype by tumor cells following TGFβ signal activation. As dual-specificity phosphatases (DUSPs) regulate ERK1/2 activity by dephosphorylation, we aimed to examine DUSPs’ expression upon TGFβ stimulation and whether DUSPs play a role in the EMT and related phenotypes promoted by TGFβ1 in A549 cells. We found that TGFβ1 stimulation led to marked changes in several DUSP proteins, including significant decreases in DUSP4 and DUSP13 expressions. We then showed that the ectopic co-expression of DUSP4/13 suppresses TGFβ1-induced ERK1/2 phosphorylation and protein levels of the EMT transcription factors Snail and Slug proteins. We then demonstrated that DUSP4/13 co-expression partially inhibited TGFβ1-promoted migration, invasion, and chemoresistance in A549 cells. Collectively, this report provides data for the involvement of DUSP4/13 in malignant phenotypes regulated by TGFβ1 in A549 cells.
•TGFβ1 suppresses expressions of DUSP4 and DUSP13.•DUSP4/13 co-expression suppresses TGFβ1-induced ERK1/2 phosphorylation, Snail and Slug proteins.•DUSP4/13 co-expression attenuates TGFβ1-promoted migration and chemoresistance.
Dual-specificity phosphatases (DUSPs) show distinct substrate preferences for specific MAPKs. DUSPs sharing a substrate preference for ERK1/2 may be classified as inducible or constitutive. In ...contrast to the inducible DUSPs which also dephosphorylate p38 MAPK and JNK in the major inflammatory pathways, constitutive DUSP6 and DUSP7 are specific to ERK1/2 and have not been studied in microglia and other immune cells to date. In the present study, we differentiated mRNA expression profiles of inducible and constitutive DUSPs that dephosphorylate ERK1/2 in microglia. Lipopolysaccharide (LPS) at 1 ng/ml induced prompt phosphorylation of ERK1/2 with peak induction at 30 min. LPS induced expression of DUSP1, DUSP2, and DUSP5 within 60 min, whereas DUSP4 expression was induced more slowly. DUSP6 and DUSP7 exhibited constitutive basal expression, which decreased immediately after LPS stimulation but subsequently returned to basal levels. The expression of DUSP6 and DUSP7 was regulated inverse to the phosphorylation of ERK1/2 in LPS-stimulated microglia. Therefore, we next investigated the correlation between DUSP6 and DUSP7 expression and ERK1/2 phosphorylation in resting and LPS-stimulated microglia. Inhibition of the ERK1/2 pathway by PD98059 and FR180204 resulted in a decrease in DUSP6 and DUSP7 expression, both in resting and LPS-stimulated microglia. These inhibitors partially blocked the LPS-induced expression of DUSP1, DUSP2, and DUSP4, but had no effect on DUSP5. Finally, we examined the role of DUSP6 activity in the downregulation of ERK1/2 phosphorylation. BCI, an inhibitor of DUSP6, increased the phosphorylation of ERK1/2. However, pretreatment with BCI inhibited the LPS-induced phosphorylation of ERK1/2. These results demonstrate that constitutive DUPS6 and DUSP7 expression was downregulated inverse to the expression of inducible DUSPs and the phosphorylation of ERK1/2 in LPS-stimulated microglia. The expression of DUPS6 and DUSP7 was mediated by ERK1/2 activity both in resting and LPS-stimulated microglia. In turn, DUSP6 suppressed the basal phosphorylation of ERK1/2, but exerted no suppressive effect on LPS-induced phosphorylation. Although DUSP6 is acknowledged as a negative regulator of the ERK1/2 pathway, such roles of DUSP6 need to be examined further in activated microglia.
•ERK1/2 phosphorylation increased immediately after LPS treatment.•Constitutive expression of DUSP6 decreased immediately after LPS treatment.•ERK1/2 mediated DUSP6 expression in resting and activated microglia.•BCI, an inhibitor of DUSP6 activity, increased basal phosphorylation of ERK1/2.•BCI pretreatment inhibited LPS-induced phosphorylation of ERK1/2.
Resident tissue macrophages (RTMs) have a broad spectrum of immune- and non-immune-related tissue-supporting activities. The roots of this heterogeneity and versatility are only beginning to be ...understood. Here, we propose a conceptual framework for considering the RTM heterogeneity that organizes the factors shaping RTM identity within four cardinal points: (1) ontogeny and the view that adult RTM populations comprise a defined mixture of cells that arise from either embryonic precursors or adult monocytes; (2) local factors unique to the niche of residence, evolving during development and aging; (3) inflammation status; and (4) the cumulative effect of time spent in a specific tissue that contributes to the resilient adaptation of macrophages to their dynamic environment. We review recent findings within this context and discuss the technological advances that are revolutionizing the study of macrophage biology.
Resident tissue macrophages (RTMs) have a broad spectrum of immune- and non-immune-related tissue-supporting activities. Ginhoux and colleagues propose a conceptual framework for considering the RTM heterogeneity that organizes the factors shaping RTM identity within four cardinal points: ontogeny, the niche of residence, inflammation status, and the cumulative effect of time spent in a specific tissue.
There are several criteria for determination of the most appropriate cut-off value in a diagnostic test with continuous results. Mostly based on receiver operating characteristic (ROC) analysis, ...there are various methods to determine the test cut-off value. The most common criteria are the point on ROC curve where the sensitivity and specificity of the test are equal; the point on the curve with minimum distance from the left-upper corner of the unit square; and the point where the Youden's index is maximum. There are also methods mainly based on Bayesian decision analysis. Herein, we show that a proposed method that maximizes the weighted number needed to misdiagnose, an index of diagnostic test effectiveness we previously proposed, is the most appropriate technique compared to the aforementioned ones. For determination of the cut-off value, we need to know the pretest probability of the disease of interest as well as the costs incurred by misdiagnosis. This means that even for a certain diagnostic test, the cut-off value is not universal and should be determined for each region and for each disease condition.
In Basque–Spanish bilinguals, statistical learning (SL) in the visual modality was more efficient on nonlinguistic than linguistic input; in the auditory modality, we found the reverse pattern of ...results. We hypothesize that SL was shaped for processing nonlinguistic environmental stimuli and only later, as the language faculty emerged, recycled for speech processing. This led to further adaptive changes in the neurocognitive mechanisms underlying speech processing, including SL. By contrast, as a recent cultural innovation, written language has not yet led to adaptations. The current study investigated whether such phylogenetic influences on SL can be modulated by ontogenetic influences on a shorter timescale, over the course of individual development. We explored how SL is modulated by the ambient linguistic environment. We found that SL in the auditory modality can be further modulated by exposure to a bilingual environment, in which speakers need to process a wider range of diverse speech cues. This effect was observed only on linguistic, not nonlinguistic, material. We conclude that ontogenetic factors modulate the efficiency of already existing SL ability, honing it for specific types of input, by providing new targets for selection via exposure to different cues in the sensory input.
Spoken language has been relevant for individual fitness in the genus Homo for sufficiently long time to enable adaptive use of auditory statistical learning (SL) ability for speech processing. By contrast, as a recent cultural innovation, written language has not yet led to adaptations of visual SL ability. The current study investigated whether such phylogenetic influences on SL can be modulated by ontogenetic influences over the course of individual development.
Glucan phosphatases are a recently discovered class of enzymes that dephosphorylate starch and glycogen, thereby regulating energy metabolism. Plant genomes encode two glucan phosphatases, called ...Starch EXcess4 (SEX4) and Like Sex Four2 (LSF2), that regulate starch metabolism by selectively dephosphorylating glucose moieties within starch glucan chains. Recently, the structures of both SEX4 and LSF2 were determined, with and without phosphoglucan products bound, revealing the mechanism for their unique activities. This review explores the structural and enzymatic features of the plant glucan phosphatases, and outlines how they are uniquely adapted to perform their cellular functions. We outline the physical mechanisms used by SEX4 and LSF2 to interact with starch glucans: SEX4 binds glucan chains via a continuous glucan‐binding platform comprising its dual‐specificity phosphatase domain and carbohydrate‐binding module, while LSF2 utilizes surface binding sites. SEX4 and LSF2 both contain a unique network of aromatic residues in their catalytic dual‐specificity phosphatase domains that serve as glucan engagement platforms and are unique to the glucan phosphatases. We also discuss the phosphoglucan substrate specificities inherent to SEX4 and LSF2, and outline structural features within the active site that govern glucan orientation. This review defines the structural mechanism of the plant glucan phosphatases with respect to phosphatases, starch metabolism and protein–glucan interaction, thereby providing a framework for their application in both agricultural and industrial settings.
Glucan phosphatases regulate energy metabolism in plants and animals via dephosphorylation of starch and glycogen. Recently, the structural mechanisms of several glucan phosphatases have been elucidated, revealing interesting adaptations permitting dephosphorylation of polyglucan substrates. Here we discuss the diverse structural bases for plant glucan phosphatase activity, which include novel mechanisms for glucan binding, catalysis, and substrate specificity.
For many applications the continuous prediction afforded by species distribution modeling must be converted to a map of presence or absence, so a threshold probability indicative of species presence ...must be fixed. Because of the bias in probability outputs due to frequency of presences (prevalence), a fixed threshold value, such as 0.5, does not usually correspond to the threshold above which the species is more likely to be present. In this paper four threshold criteria are compared for a wide range of sample sizes and prevalences, modeling a virtual species in order to avoid the omnipresent error sources that the use of real species data implies. In general, sensitivity–specificity difference minimizer and sensitivity–specificity sum maximizer criteria produced the most accurate predictions. The widely-used 0.5 fixed threshold and Kappa-maximizer criteria are the worst ones in almost all situations. Nevertheless, whatever the criteria used, the threshold value chosen and the research goals that determined its choice must be stated.
The performance of a diagnostic test in the case of a binary predictor can be evaluated using the measures of sensitivity and specificity. However, in many instances, we encounter predictors that are ...measured on a continuous or ordinal scale. In such cases, it is desirable to assess performance of a diagnostic test over the range of possible cutpoints for the predictor variable. This is achieved by a receiver operating characteristic (ROC) curve that includes all the possible decision thresholds from a diagnostic test result. In this brief report, we discuss the salient features of the ROC curve, as well as discuss and interpret the area under the ROC curve, and its utility in comparing two different tests or predictor variables of interest.
It is estimated that 1 billion people around the world are vitamin D deficient. Vitamin D deficiency has been linked to various inflammatory diseases. However, the mechanism by which vitamin D ...reduces inflammation remains poorly understood. In this study, we investigated the inhibitory effects of physiologic levels of vitamin D on LPS-stimulated inflammatory response in human blood monocytes and explored potential mechanisms of vitamin D action. We observed that two forms of the vitamin D, 1,25(OH)(2)D(3), and 25(OH)D(3), dose dependently inhibited LPS-induced p38 phosphorylation at physiologic concentrations, IL-6 and TNF-α production by human monocytes. Upon vitamin D treatment, the expression of MAPK phosphatase-1 (MKP-1) was significantly upregulated in human monocytes and murine bone marrow-derived macrophages (BMM). Increased binding of the vitamin D receptor and increased histone H4 acetylation at the identified vitamin D response element of the murine and human MKP-1 promoters were demonstrated. Moreover, in BMM from MKP1(-/-) mice, the inhibition of LPS-induced p38 phosphorylation by vitamin D was completely abolished. Vitamin D inhibition of LPS-induced IL-6 and TNF-α production by BMM from MKP-1(-/-) mice was significantly reduced as compared with wild-type mice. In conclusion, this study identified the upregulation of MKP-1 by vitamin D as a novel pathway by which vitamin D inhibits LPS-induced p38 activation and cytokine production in monocytes/macrophages.
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