In addition during the preparation of this manuscript

In addition, during the preparation of this manuscript, Oka et al. [7] demonstrated that LPA acts as receptor ligand for GPR35 and that LPA is more potent than KYNA in eliciting a calcium mobilization (EC50: 30nM vs. 39μM for LPA and KYNA, respectively). Other endogenous GPR35 ligands, therefore, might be more potent than KYNA and zaprinast also in modulating cytokine release from iNKT cells. Finally, increased levels of plasma kynurenines are present in those diseases in which the involvement of iNKT cells has been demonstrated, such as autoimmune diseases [25], multiple sclerosis (MS) [35], inflammatory bowel disease [32], and virus infections [36]. While an accumulation of quinolinic or 3-hydroxyanthranilic CORM-3 [37] can lead to a down-regulation of immune cell functions [38] by cytotoxicity, an increased level of KYNA, which is not a toxic compound, cannot affect immune cells by the same mechanism. Here we propose that KYNA might modulate cytokine release from human iNKT cells by a GPR35-mediated mechanism (Fig. 3) and that GPR35 might represent one of the key factors for controlling iNKT cell-mediated immune responses. In conclusion, we demonstrate that human iNKT cells express GPR35 and that the functional responses of this receptor can be pharmacologically modulated. The pharmacological modulation of this receptor might be useful in those situations were iNKT cells participate in the development of beneficial (e.g., tumors and infections, autoimmune diseases, self-tolerance) or detrimental (e.g., airway hypersensitivity, atherosclerosis, fetus rejection) immune responses [14].
Acknowledgments
This study was supported by grants from University of “Piemonte Orientale Amedeo Avogadro” and “Regione Piemonte” (Italy).
Introduction Many G-protein coupled receptors involved in pain and addiction are pharmacologically and biochemically well characterized, but some orphan receptors like GPR35 and GPR55, with homology to known receptors for drugs of abuse, remain poorly characterized. GPR35 is emerging as an important target in pain (spinal antinociception as well as inflammatory pain), heart disease, asthma, inflammatory bowel disease and cancer, areas with unmet medical needs. To date, quite a few agonists and antagonists have been discovered for GPR35 (Heynen-Genel et al., 2010c, Milligan, 2011). While kynurenic acid was suggested to be an endogenous ligand for GPR35, so was 2-arachidonyl lysophosphatidic acid (LPA) (Oka et al., 2010, Wang et al., 2006). The GPR55 receptor is a promising target in inflammatory and neuropathic pain (Staton et al., 2008), as well as in bone development (Whyte et al., 2009). While several studies indicate that GPR55 activation is pro-carcinogenic (Andradas et al., 2011, Ford et al., 2010, Pineiro et al., 2011), others report anticarcinogenic activity (Huang et al., 2011). GPR55 has been suggested to be a cannabinoid receptor, but is quite clearly also a receptor for lysophosphatidylinositol (Henstridge et al., 2011, Oka et al., 2007, Ryberg et al., 2007, Sharir and Abood, 2010). Recently, additional agonists and antagonists have been discovered for GPR55 (Brown et al., 2011, Heynen-Genel et al., 2010a, Heynen-Genel et al., 2010b). Here, we review what is known about GPR35 and GPR55 and their relationships to cannabinoid and lysophospholipid receptors.
Expression profiles of GPR35 and GPR55 GPR35 was first identified in 1998 from rat intestine as a class A (rhodopsin-like) G protein-coupled receptor that contains 309 amino acids (O'Dowd et al., 1998). A splice variant, GPR35b, containing an N-terminal expansion of 31 amino acids was later discovered from a cDNA library produced from human gastric cancer cells (Okumura et al., 2004). Because GPR35b was able to transform NIH-3T3 cells, it was suggested that it might be oncogenic and play a role in gastric cancer development (Okumura et al., 2004). The significant expression of GPR35 in human small intestine, colon and stomach was confirmed subsequently by Imielinski et al. in 2009 (Imielinski et al., 2009). Other rat tissues also express GPR35, such as lung, uterus, dorsal root ganglion (Ohshiro et al., 2008, Taniguchi et al., 2006) and spinal cord (Cosi et al., 2011). Wang et al. reported GPR35 expression in the spleen and white cells of both human and mice (Wang et al., 2006). Furthermore human mast cells, basophils and eosinophils also express GPR35 (Yang et al., 2010). GPR35 expression in immune cells was later expanded to peripheral monocytes and primary macrophages as well (Barth et al., 2009, Sparfel et al., 2010). In failing heart cells, an enhanced expression of GPR35 was found in a global gene expression profiling study (Min et al., 2010).