Plasma IL-33 levels are decreased in patients with high-risk myelodysplastic syndrome and show no correlation with pro-inflammatory IL-6 levels.

Aberrant inflammatory signaling has been shown to be a key pathogenic driver in myelodysplastic syndromes (MDS). Abnormal IL-33 expression has been implicated in inflammatory, immune-related disorders and, some tumors. However, its role in MDS remains widely unknown. This study aimed to evaluate the relationship between plasma levels of IL-33, clinical and prognostic data and, IL-6 levels in 101 patients with MDS. A comparative group of 59 healthy individuals was also evaluated. Plasma levels of cytokines were determined by enzyme-linked immunosorbent assay. Lower levels of IL-33 were found in patients with MDS when compared to the control group (p = 0.001), mainly in patients with more advanced stages of the disease and worse prognosis. No significant correlation between the levels of IL-33 and IL-6 was observed (r = 0.175; p = 0.081). These results reinforce the close association between immunological disorders and the pathogenesis of MDS. A greater understanding of the role of inflammatory cytokines in the disease can potentially provide new diagnosis and prognosis markers and new therapeutic targets.

Immune Dysregulation and Recurring Mutations in Myelodysplastic Syndromes Pathogenesis.

Myelodysplastic syndromes (MDS) are clonal stem cell malignancies characterized by ineffective hematopoiesis leading to peripheral cytopenias and variable risk of progression to acute myeloid leukemia. Inflammation is associated with MDS pathogenesis. Several cytokines, reactive species of oxygen/nitrogen and growth factors are directly or indirectly involved in dysfunction of the MDS bone marrow (BM) microenvironment. Mutations in genes mainly regulating RNA splicing, DNA methylation and chromatin accessibility, transcription factors, signal transduction and the response to DNA damage contribute to ineffective hematopoiesis, genomic instability and MDS development. The inflammation-associated DNA damage in hematopoietic stem cells may also contribute to MDS development and progression with aggressive clinical characteristics. Many studies have aimed at clarifying mechanisms involved in the activity of immature myeloid cells as powerful modulators of the immune response and their correlation with aging, autoimmunity, and development of cancer. In this review, we explore recent advances and accumulating evidence uniting immune dysregulation, inflammaging and recurring mutations in the pathogenesis of MDS.

Interleukin-8 and nuclear factor kappa B are increased and positively correlated in myelodysplastic syndrome.

The pathogenesis of myelodysplastic syndromes (MDS) is complex and depends on the interaction between aberrant hematopoietic cells and their microenvironment, probably including aberrations in cytokines and their signaling pathways. To evaluate interleukin-8 (IL-8) plasma levels and nuclear factor kappa B (NF-kB) in patients with MDS and to test possible correlation between IL-8 and NF-Kb, a total of 45 individuals were analyzed: 25 consecutive adult de novo MDS patients and 20 sex and age-matched healthy elderly volunteers. IL-8 analysis was performed by ELISA and activity of NF-kB by chemiluminescent assay. MDS patients showed higher level of IL-8 when compared to controls (p = 0.006). Patients aged 75 and above showed even higher levels (p = 0.035). NF-kB activity was significantly elevated in MDS patients when compared to controls (p < 0.0001) and higher in patients older than 75 years (p = 0.047). NF-kB activity was associated with higher serum ferritin (p = 0.042) and higher percentage of blasts (p = 0.028). A significant positive correlation between IL-8 and NF-kB was demonstrated (r = 0.480; p = 0.015). Many pathways involved in pathophysiology of MDS have been recently described, suggesting that an inflammatory process may act as a pathogenic driver. In this study, significantly elevated levels of IL-8 and NF-kB were demonstrated in MDS patients, with positive association of NF-kB with some markers of poor prognosis. A positive correlation between IL-8 and NF-kB suggests they cooperate as part of a complex networking of immune and inflammatory factors involved in MDS.

Myelodysplastic syndrome patients present more severe respiratory muscle impairment and reduced forced vital capacity: Is disordered inflammatory signaling the culprit?

BACKGROUND/OBJECTIVES: The ageing process is associated with gradual decline in respiratory system performance. Anemia is highly prevalent among older adults and usually associated with adverse outcomes. Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic malignancies with increasing incidence with age and characterized by anemia and other cytopenias. The main objectives of this study were to evaluate respiratory muscle strength and lung function in elderly patients with anemia, compare data between myelodysplastic syndromes and non-clonal anemias and evaluate the influence of serum IL-8 level and NF-kB activity on deteriorate pulmonary function in this specific population. PARTICIPANTS: Individuals aged 60 and older with anemia secondary to MDS, non-clonal anemia and healthy elderly individuals. MEASUREMENTS: Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/ FVC ratio were measured by spirometry. Respiratory muscle strength was evaluated by maximal static respiratory pressures measurement. IL-8 analysis was performed by ELISA and activity of NF-kB by chemiluminescent assay. RESULTS: Mean Hb concentration was comparable between patients with anemia. Significant differences were detected between all patients with anemia and controls for maximum-effort inspiratory mouth pressure (PImax) and also for maximum-effort expiratory mouth pressure (PEmax). The MDS group recorded a significantly lower PImax and PEmax percent predicted when compared to non-clonal anemia group. For FVC and FEV1, a significant difference was found in anemic patients, with even significantly lower values for FVC and FEV1 in MDS group. No significant differences were detected for PImax and PEmax and spirometry parameters when anemic patients were stratified according to the degree of anemia. A significant negative impact in FVC (% pred), PImax (% pred) and PEmax (% pred) was observed in patients with MDS and higher levels of IL-8 or increased activity of NF-kB. CONCLUSION: A negative impact of anemia, independent of its degree, was demonstrated in respiratory muscle strength and lung function particularly in MDS. The well known elevated proinflammatory cytokines in MDS patients were proposed to play a role as was demonstrated by detrimental effect of higher IL-8 and NF-kB in pulmonary function tests in this population.