CO, an Immuno- and Neuromodulator

Abstract

Two groups report signaling mediated by carbon monoxide (CO), a gas much better known for its ability to displace oxygen in hemoglobin, which can result in death. Morse et al. suggest that CO produced by stress-stimulated heme oxygenase-1 (HO-1) may inhibit cytokine production, resulting in a protective effect in a mouse model of sepsis. Exposure of mice to CO before injection with lipopolysaccharide (LPS) decreased morbidity and decreased circulating cytokine levels [interleukin-6 (IL-6) and IL-1β]. Analysis of CO-exposed cultured macrophages suggested that the decrease in cytokine production was due to decreased transcription. Analysis of reporter gene expression and electrophoretic mobility shift assays indicated that CO disrupted activity of the AP-1 transcription factor complex, specifically the complex containing c-Fos. Finally, CO appeared to inhibit Jun-N-terminal kinase signaling, because the Jnk–/– mice were not rescued from injected LPS-induced death by CO, nor were inflammatory cytokine levels triggered by nonlethal doses of LPS decreased by treatment with CO. Boehning et al. show that in neurons CO production is stimulated by activity-dependent phosphorylation of HO-2. Using in vitro phosphorylation assays, phosphopeptide mapping, and site-directed mutagenesis, the authors determined that a single serine in HO-2 was phosphorylated by casein kinase 2 (CK2). In hippocampal cultures and cultured olfactory neurons, HO-2 activity and phosphorylation were stimulated by phorbol esters and odorant stimulation, respectively. Pharmacologic analysis suggested that the upstream pathways leading to CK stimulation of HO-2 were different in the two neuronal cultures. The final system where CO-mediated neurotransmission was analyzed was dissected internal anal sphincter (IAS) preparations, in which relaxation is known to be mediated by nonadrenergic noncholinergic transmission involving both nitric oxide and CO. Treatment with CK2 inhibitors reduced IAS relaxation in response to electric field stimulation, and the effectiveness of the tested compounds correlated with their potency as CK2 inhibitors. Thus, neuronal activity-dependent stimulation of CK2 appears to be a common mechanism by which the synthesis of CO can be achieved in neurons.D. Morse, S. E. Pischke, Z. Zhou, R. J. Davis, R. A. Flavell, T. Loop, S. L. Otterbein, L. E. Otterbein, A. M. K. Choi, Suppression of inflammatory cytokine production by carbon monoxide involves the JNK pathway and AP-1. J. Biol. Chem. 278, 36993-36998 (2003). [Abstract] [Full Text]D. Boehning, C. Moon, S. Sharma, K. J. Hunt, L. D. Hester, G. V. Ronnett, D. Shugar, S. H. Snyder, Carbon monoxide neurotransmission activated by CK2 phosphorylation of heme oxygenase-2. Neuron 40, 129-137 (2003). [Online Journal]