Serum Levels of the Proinflammatory Cytokines Interleukin-1 Beta (IL-1β), IL-6, IL-8, IL-10, Tumor Necrosis Factor Alpha, and IL-12(p70) in Malian Children with SeverePlasmodium falciparumMalaria and Matched Uncomplicated Malaria or Healthy Controls

Abstract

Inflammatory cytokines play an important role in human immune responses to malarial disease. However, the role of these mediators in disease pathogenesis, and the relationship between host protection and injury remains unclear. A total of 248 cases of severe Plasmodium falciparum malaria among children aged 3 months to 14 years residing in Bandiagara, Mali, were matched to cases of uncomplicated malaria and healthy controls. Using modified World Health Organization criteria for defining severe malaria, we identified 100 cases of cerebral malaria (coma, seizure, and obtundation), 17 cases of severe anemia (hemoglobin, <5 g/dl), 18 cases combined cerebral malaria with severe anemia, and 92 cases with hyperparasitemia (asexual trophozoites, >500,000/mm3). Significantly elevated levels (given as geometric mean concentrations in picograms/milliliter) of interleukin-6 (IL-6; 485.2 versus 54.1; P = <0.001), IL-10 (1,099.3 versus 14.1; P = <0.001), tumor necrosis factor alpha (10.1 versus 7.7; P = <0.001), and IL-12(p70) (48.9 versus 31.3; P = 0.004) in serum were found in severe cases versus healthy controls. Significantly elevated levels of IL-6 (485.2 versus 141.0; P = <0.001) and IL-10 (1,099.3 versus 133.9; P = <0.001) were seen in severe malaria cases versus uncomplicated malaria controls. Cerebral malaria was associated with significantly elevated levels of IL-6 (754.5 versus 311.4; P = <0.001) and IL-10 (1,405.6 versus 868.6; P = 0.006) compared to severe malaria cases without cerebral manifestations. Conversely, lower levels of IL-6 (199.2 versus 487.6; P = 0.03) and IL-10 (391.1 versus 1,160.9; P = 0.002) were noted in children with severe anemia compared to severe malaria cases with hemoglobin at >5 g/dl. Hyperparasitemia was associated with significantly lower levels of IL-6 (336.6 versus 602.1; P = 0.002). These results illustrate the complex relationships between inflammatory cytokines and disease in P. falciparum malaria.

Increased circulating interleukin (IL)-23 in children with malarial anemia: In vivo and in vitro relationship with co-regulatory cytokines IL-12 and IL-10

“…Although IL-23 and IL-12 share the p40 subunit [17], levels of IL-23 were elevated in children with malarial anemia, while plasma IL-12 concentrations progressively declined with increasing anemia severity. The decrease in IL-12 with increasing disease severity parallels previous findings in African children residing in areas with intense malaria transmission [12][13][14]29,[43][44][45]. In addition, examination of the IL-12 to IL-23 ratio revealed that SMA is characterized by low levels of IL-12 relative to IL-23.…”

Innate Immune Responses to Human Malaria: Heterogeneous Cytokine Responses to Blood-Stage Plasmodium falciparum Correlate with Parasitological and Clinical Outcomes

“…A predominantly proinflammatory response was associated with more rapid control of parasite growth but only at the cost of developing clinical symptoms. These observations strongly support the conclusions of several correlative clinical and epidemiological studies that have also suggested that proinflammatory responses might be causally associated with both clearance of parasites and clinical disease (14,22,33). Conversely, subjects in group 3 who had no detectable inflammatory response but the highest levels of TGF-␤ were less able to control parasite growth (30) but hardly ever reported a fever or feverishness, again supporting data from studies in malaria endemic populations that anti-inflammatory activity is associated with less severe clinical symptoms (22).…”

“…IFN-␥ is the key inducer of the immune effector mechanisms that are essential for initial control of both pre-erythrocytic and blood-stage malaria infections (8,9), but there is evidence that IFN-␥ levels need to be carefully balanced to avoid immune pathology (10,11). In vivo, TNF-␣ production is associated with parasite clearance and resolution of fever (12), but elevated levels of TNF-␣ (13) and IL-6 (14,15) have also been associated with cerebral malaria. A priori, one would expect a crucial role for IL-12-and possibly also IL-18 -in initiation of the inflammatory cytokine cascade.…”

Evaluating antidisease immunity to malaria and implications for vaccine design

“…The cascade of cytokines released during the erythrocytic stages of infection, particularly pyrogenic cytokines such as TNF‐ α , IL‐1 β and IL‐6,5, 60, 82, 83, 84, 85 cause acute inflammation, which mediates immunopathology 4, 5, 60, 86, 87, 88. These cytokines are necessary for several antiparasitic effector processes, such as skewing the T‐cell response to a more pronounced T helper type 1 (Th1) response during infection,89, 90 directly killing or inhibiting parasite growth, as has been observed for TNF‐ α and IFN‐ γ, 91 and indirectly killing parasites by activating phagocytic cells 85, 91.…”