Cellular modulator

International study with Brazilian participation shows that nitric oxide present in an organism can alter the action of cells involved in inflammation in autoimmune illnesses

By Fábio de Castro

Agência FAPESP – Nitric Oxide (NO) produced by many different cells in the human body can be an endogenous regulator of T helper 17 cells (Th17), according to a new study performed by an international group with Brazilian participation. In preventing the proliferation of Th17 cells, NO has the potential capacity to control an autoimmune illness.

NO is a molecule known for its involvement in the control of pathogenic microorganisms. T cells are white globules involved with the immune response against tumors and infectious agents. Th cells, even though they neither perform phagocytosis nor have cytotoxic activity, are responsible for activating and driving other defense cells in the organism.

The study was published in the National Academy of Sciences Proceedings magazine. The study included scientists from the Ribeirão Preto College of Pharmaceutical Sciences, (FCFRP), the Ribeirão Preto School of Medicine (FMRP)—both of which are part of the Universidade de São Paulo (USP)—and from the University of Glasgow (Scotland) and  Aichi Gakuin University in Nagoya (Japan).

According to one of the Brazilian authors, Sandra Fukada (professor of pharmacology at FCFRP-USP) the study utilized in vitro and in vivo experiments to show that NO can be an endogenic regulator capable of blocking the spread of Th17 cells.

“We managed to show that NO regulates the differentiation and spread of Th17 cells. This is relevant because these cells have been implicated in the development of diverse autoimmune illnesses. If we manage to control them, we could potentially alter these illnesses,” Fukada told Agência FAPESP.

The researcher participated in the study during her post doctorate at the University of Glasgow, between 2008 and 2010. Fukada also did two post-doctorates at USP, one between 2006 and 2007 with a FAPESP fellowship and the other between 2004 and 2006 with a scholarship from the National Council of Technological and Scientific Development (CNPq). In 2004 she also finished her doctorate at USP with a FAPESP fellowship.

According to her, the international literature had already shown that NO is a key mediator in different biological functions. The group with which she performed the study in Scotland had previously published that in small quantities, NO potentizes the polarization of another T helper subtype, the Th1.

The group had also described that NO in large doses was able to induce another subtype of T cells with immunosuppressant function, the T regulator cells induced by NO (NO-Tregs).

“Considering that NO is capable of modulating Th1 and Treg cells, the question came up: Could it be that NO has some role in activating Th17 cells and, as a result, over autoimmune illnesses?” she queried.

Multiple sclerosis

The scientists verified that NO inhibits the proliferation and function of th17 cells in vitro. The group suggested that one of the probable mechanisms for this effect is that NO inhibits the expression of the aryl hydrocarbon receptor (AHR) which, in turn, is important for differentiating Th17 cells.

To complement the in vitro studies on the effects of NO on the Th15 cells, the scientists also performed in vivo experiments using the Experimental autoimmune encephalomyelitis (EAE) model in animals deficient in one of the enzymes that synthesize NO, the nitric oxide synthase 2 (NOS2), which is expressed under inflammatory conditions. According to Fukada, the encephalomyelitis animal model is similar to multiple sclerosis in humans.

“The NOS2 deficient animals presented a more severe form of the disease in comparison with those that had normal NO levels. At the same time, we verified that these animals had high AHR and Th17 levels. This suggests that NO modulates the proliferation of the Th17 cells that, in turn, regulate the autoimmune encephalomyelitis,” she said.

The article “Regulation of type 17 helper T-cell function by nitric oxide during inflammation” (doi/10.1073/pnas.1100667108), by Wanda Niedbala and others can be read by PNAS subscribers at www.pnas.org/content/early/2011/05/11/1100667108.abstract.