Regulation of chemokine production by the oxidative metabolism of L-arginine in a human mixed lymphocyte reaction.
Previous studies have shown that during the development of a mixed lymphocyte reaction (MLR) levels of the chemotactic cytokines IL-8 and MCP-1 (members of the C-X-C and C-C supergene families, respectively) increase in a time-dependent fashion, and that the production of these chemokines correlates with the magnitude of responsiveness to alloantigen. Furthermore, the responsiveness to alloantigen in the context of a MLR has been shown to be regulated by the oxidative metabolism of L-arginine. We postulated that competitive antagonism of the L-arginine metabolic pathway in a human MLR may alter the production of members of the C-C and C-X-C chemokine families. To test this hypothesis, mononuclear cells were isolated from healthy individuals and subjected to a one-way MLR in the presence or absence of varying concentrations of an L-arginine competitive inhibitor, NG-methyl-L-arginine (NMA: 50 to 500 microM). When the MLR was performed in the presence of NMA (500 microM), the production of IL-8 increased twofold (P < 0.05) and ENA-78 increased fivefold (P < 0.05), while MCP-1 and MIP-1 alpha were not significantly altered. These findings suggest that NMA, an inhibitor of the L-arginine metabolic pathway, may regulate the production of specific C-X-C chemokines, IL-8 and ENA-78, during a MLR. In contrast, the production of MCP-1 and MIP-1 alpha, members of the C-C chemokine family, does not appear to be regulated by this inhibitor of the oxidative metabolism of L-arginine in the context of a MLR.
Orens
J B
JB
Department of Medicine, University of Michigan, Ann Arbor.
Lukacs
N W
NW
Kunkel
S L
SL
Burdick
M D
MD
Wilke
C A
CA
Walz
A
A
Strieter
R M
RM
D001120:Arginine / Q000378:metabolism*; D002478:Cells, Cultured; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D054365:Chemokine CXCL5; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000378:metabolism / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D016209:Interleukin-8 / Q000031:analogs & derivatives / Q000378:metabolism; D007959:Lymphocyte Culture Test, Mixed; D019402:Macrophage Inflammatory Proteins; D015846:Monokines / Q000378:metabolism; D010084:Oxidation-Reduction
C486263:CXCL5 protein, human; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D054365:Chemokine CXCL5; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D016207:Cytokines; D016209:Interleukin-8; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D001120:Arginine