Nitric oxide (NO) is a potent free radical produced by nitric oxide synthase (NOS) [
1,
2]. Activity of inducible NOS (iNOS), the high-output, cytokine-modulated isoform of NOS varies very widely in different species and cell types [
3]. In humans, endothelia, hepatocytes and smooth muscle cells are the major contributing cells, while monocytes/macrophages appear to produce no or little NO in response to IFN-gamma, TNF-alpha, or IL-1beta [
3‐
6], highly effective stimuli in murine macrophages [
7]. Data indicate that severe murine and human malaria is accompanied by increased iNOS activity and production of NO [
8,
9], considered to be beneficial because NO was shown to kill parasites [
10,
11]. Secondly, elevated NO levels in the blood of malaria patients were associated with inhibition of adhesion of parasites to endothelia [
12]. Increased NO levels and protection against malaria have been linked to a single nucleotide polymorphism in the promoter of iNOS gene termed NOS2
Lambaréné (G-954C) mutation [
13]. Blood monocytes of those protected heterozygotes had a 7-fold higher baseline iNOS activity [
13]. Recently, it has been shown that phagocytosis of
P. falciparum haemozoin (HZ) and synthetic HZ (sHZ, beta-haematin) by murine phagocytes significantly increased IFN-gamma-mediated iNOS expression and NO production [
14], offering a mechanistic link to the increased, possibly protective NO levels observed in clinical malaria. Here the authors analysed iNOS mRNA, protein expression and NO production in HZ/sHZ-fed immuno-purified human monocytes and were unable to find any iNOS expression and NO production even after maximal stimulation by IFN-gamma, TNF-alpha, IL-1beta and LPS, whereas these stimuli were highly effective in HZ-laden murine phagocytes. Lack of iNOS response by human monocytes shown here casts doubt on the capacity of those cells to produce NO in vivo and mediate protection in clinical malaria, and suggests caution in transferring data obtained with non-human cells to human malaria.