Increased lymphotoxin in human malarial serum, and the ability of this cytokine to increase plasma interleukin-6 and cause hypoglycaemia in mice: implications for malarial pathology.
The origin of illness and pathology in malaria is now largely attributed to high levels of circulating tumour necrosis factor (TNF), released from cells of macrophage lineage after triggering by the products of malarial schizogony. The role of lymphocytes and their products in malarial pathology is not yet known. This paper reports the presence of a related cytokine, lymphotoxin, which is produced only by lymphocytes, in the serum of malarial patients. This is the first report of raised serum levels of lymphotoxin in a systemic disease state. When injected into mice, recombinant human lymphotoxin induced hypoglycaemia and increased serum levels of interleukin-6. These changes, which are seen in severe experimental and human malaria, were also provoked by TNF. Both of these cytokines acted synergistically with interleukin-1, which has also been reported to be raised in malaria, to produce these alterations. These observations imply that lymphotoxin, as well as TNF, may contribute to the hypoglycaemia and raised serum interleukin-6 observed in malaria. This reduces the likelihood of effectively blocking the pathology of this disease by the use of neutralizing antibody directed against just one member of this family of functionally overlapping mediators.
Clark
I A
IA
Division of Biochemistry and Molecular Biology, School of Life Sciences, Australian National University, Canberra, ACT.
Gray
K M
KM
Rockett
E J
EJ
Cowden
W B
WB
Rockett
K A
KA
Ferrante
A
A
Aggarwal
B B
BB
D000293:Adolescent; D000328:Adult; D000818:Animals; D001681:Biological Assay; D001786:Blood Glucose / Q000187:drug effects; D005260:Female; D006801:Humans; D007003:Hypoglycemia / Q000097:blood / Q000209:etiology*; D015850:Interleukin-6 / Q000097:blood*; D008233:Lymphotoxin-alpha / Q000097:blood* / Q000494:pharmacology; D016778:Malaria, Falciparum / Q000097:blood* / Q000150:complications*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001786:Blood Glucose; D015850:Interleukin-6; D008233:Lymphotoxin-alpha; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha