Nitric oxide (NO), the molecule of the year 1992, is gaining recognition as an important biological mediator. Its multitude of physiologic and pathophysiologic functions result from both a wide distribution of synthesis and diverse mechanisms of action. Besides its functions as a potent vasodilator and neurotransmitter, NO is important in inflammation and immunity. Both beneficial and detrimental consequences of induced synthesis have been discovered. Information is now accumulating on the regulation and function of induced NO. The recent cloning of human inducible NO cDNA should assist in defining the role of inducible NO in human physiology and pathophysiology.

Inflammation, immunoregulation, and inducible nitric oxide synthase

Role of nitric oxide in parasitic infections.

The arginine-nitric oxide pathway: a target for new drugs.

The presence of a negatively charged residue in the transmembrane domain of DAP12 precludes its cell surface expression in the absence of a partner receptor containing a positive charge in its transmembrane domain. We utilized this property of DAP12 to screen a BALB / c macrophage cDNA library for novel molecules that induce cell surface expression of DAP12. By this method, we cloned a cell surface receptor with a single Ig (V) domain, a transmembrane lysine residue, and a short cytoplasmic domain. By homology screening of BALB / c macrophage libraries, we identified a second cDNA for a highly homologous receptor. These receptors appear to be the mouse orthologues of a recently identified human cDNA, TREM-2, so we have designated the receptors as mouse TREM-2a and TREM-2b. By Northern blotting, transcripts for TREM-2 were found in each of three macrophage cell lines but not in a variety of other hematopoietic cell lines. We further demonstrate that TREM-2a is associated with endogenous DAP12 in macrophage cells, and cross-linking of TREM-2a on the surface of macrophages leads to the release of nitric oxide. Our studies define TREM-2 as a receptor family in mouse macrophages and demonstrate the capacity of these receptors to activate macrophage function through DAP12.

Cloning and characterization of a novel mouse myeloid DAP12-associated receptor family

Nitric oxide (NO) is an important effector molecule of the immune system in eliminating numerous pathogens. Peritoneal macrophages from Trypanosoma brucei brucei-infected mice express type II NO synthase (NOS-II), produce NO, and kill parasites in the presence of L-arginine in vitro. Nevertheless, parasites proliferate in the vicinity of these macrophages in vivo. The present study shows that L-arginine availability modulates NO production. Trypanosomes use L-arginine for polyamine synthesis, required for DNA and trypanothione synthesis. Moreover, arginase activity is up-regulated in macrophages from infected mice from the first days of infection. Arginase competes with NOS-II for their common substrate, L-arginine. In vitro, arginase inhibitors decreased urea production, increased macrophage nitrite production, and restored trypanosome killing. In vivo, a dramatic decrease in L-arginine concentration was observed in plasma from infected mice. In situ restoration of NO production and trypanosome killing were observed when excess L-arginine, but not D-arginine or L-arginine plus N(omega)-nitro-L-arginine (a NOS inhibitor), was injected into the peritoneum of infected mice. These data indicate the role of L-arginine depletion, induced by arginase and parasites, in modulating the L-arginine-NO pathway under pathophysiological conditions.

Jean Loup Lemesre

Papers

Nitric oxide-mediated cytostatic activity on Trypanosoma brucei gambiense and Trypanosoma brucei brucei.