Strong inflammatory response and Th1-polarization profile in children with acute lymphoblastic leukemia without apparent infection

Abstract

Children with acute lymphoblastic leukemia (ALL) often present fever. Febrile states are usually associated with infectious processes that generate an inflammatory response involving various molecules, including cytokines. However, an inflammatory response may also occur in the absence of infection. We hypothesized that the levels of inflammatory cytokines are increased in children with ALL without apparent infection. The serum levels of 13 cytokines in 99 patients with ALL and 48 non-oncological patients without apparent infection were measured using multiplex analyte profiling technology (Luminex®). The concentration of circulating pro-inflammatory cytokines associated with fever was similar between patients with ALL and fever at diagnosis and those without fever. The levels of tumor necrosis factor α, interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1 (MCP-1) and IL-10 were higher in patients with ALL vs. the control group (P<0.05). Moreover, the levels of the T helper 1 (interferon‑γ and IL-12) cytokines were higher in patients with ALL vs. the control group. Transforming growth factor β was lower in patients with ALL vs. the control group (P<0.05). The levels of IL-1β, IL-2, IL-4, IL-13, and IL-17 were similar in the two groups. Our results indicate that the circulating levels of seven of the important studied cytokines are elevated in patients with newly diagnosed ALL without apparent infection, reflecting a strong and deregulated inflammatory state in this disease, with a Th1-polarization profile.

The NLRP3 Inflammasome and Its Role in the Pathogenicity of Leukemia

“…IL-1β is thought to increase cell proliferation by stimulating the production of other growth factors and cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) [19,24]. Additionally, in ALL patients, a highly dysregulated inflammatory state can be detected, which is characterized by elevated circulating levels of proinflammatory cytokines such as IL-1β, TNF-α and IL-6 [25]. Hematopoietic leukemic cells from the bone marrow of B-cell acute lymphocytic leukemia (B-ALL) are involved in the production of proinflammatory mediators and growth factors in ALL patients.…”

Prognostic Relevance of Expression of EMP1, CASP1, and NLRP3 Genes in Pediatric B-Lineage Acute Lymphoblastic Leukemia

“…High STAT5 expression leads to more aggressive disease and mediates IL-2 induced glucocorticoid resistance ( 37 ). Inflammatory responses are dysregulated in ALL ( 38 ) and chronic inflammation in addition to genetic changes aids in the development of myeloid leukemia ( 39 ). Hypoxia is common in the bone-marrow environment.…”

Induction chemotherapy reduces extracellular heat shock protein 72 levels, inflammation, lipoperoxidation and changes insulin sensitivity in children and adolescents newly diagnosed with acute lymphoblastic leukemia

“…Moreover, the levels of the T helper 1 (interferon-γ and IL-12) cytokines are higher in patients with ALL while transforming growth factor β is lower in ALL. These results indicate that the circulating levels of cytokines are elevated in patients with newly diagnosed ALL without apparent infection, reflecting a strong and deregulated inflammatory state in this disease, with a Th1-polarization profile [ 39 ]. Since the sympathetic nervous system is involved on the activation of this polarization, the increased tone of this system may explain this immune behavior in ALL.…”

“…These correlations are not merely mathematical, they have an important biological significance. As the immune system becomes highly activated, the increased inflammatory molecules can stimulates the release of other signaling molecules such as CRP and eHSP72 (also inflammatory) [ 28 , 39 , 40 ]. With more inflammatory cytokines, more inflammation is produced, in a positive feedback loop mechanism.…”