SOCS3 expression in classically activated rat macrophages impairs arginase expression

Well, after nearly dismissing my ideas on SOCS and leishmaniasis in my last post, I came across this interesting paper by Liu and colleagues that rekindled the old flame a bit. Published in the Journal of Immunology in May 2008, they show that SOCS3 knockdown by RNA interference in classically activated rat macrophages coincided with an upregulation of alternative activation makers such as arginase.

Liu Y, Stewart KN, Bishop E, Marek CJ, Kluth DC, Rees AJ, Wilson HM. Unique expression of suppressor of cytokine signaling 3 is essential for classical macrophage activation in rodents in vitro and in vivo. J Immunol. 2008 May 1;180(9):6270-8.


This brings me back to my question: would SOCS3 shut down STAT3 (IL-6-induced arginase) and IRS-2 signalling and SOCS5 shut down STAT6 (IL-4-induced arginase) signalling so that arginase activity would drop to levels below those able to support parasite proliferation? What role does S-adenosylmethionine play in all this - control of SOCS expression via DNA methylation versus polyamine synthesis of spermine and spermidine? Untangling all this experimentally will no doubt be a bit tricky, because the effects of SOCS on macrophages should be kept separate from effects of SOCS on other cell types.

I would suggest to start in vitro and to compare the effects of RNAi mediated by siRNA against SOCS1, SOCS3, SOCS5, DNA (cytosine-5-)-methyltransferase 1, DNA (cytosine-5-)-methyltransferase 3 alpha, DNA (cytosine-5-)-methyltransferase 3 beta, S-adenosylmethionine synthetase, ornithine decarboxylase, S-adenosylmethionine decarboxylase, spermidine synthase and spermine synthase in respect to parasite development. An interesting side project would be to find out whether or not culturing macrophages in the presence of increased S-adenosylmethionine concentrations leads to higher parasite proliferation. The in vivo experiments that spring to mind are inducible macrophage-specific expression of transgenes: either SOCS-specific shRNA in resistant mice or SOCS in susceptible mice. Whilst it would be preferable if the gene expression was not leaky, I think my wish list is getting slightly too demanding, but if anyone out there thinks that some of these ideas are useful and has the means to set up the necessary experiments please feel welcome to do so. I believe that the sooner the scientific community can come up with new affordable drugs against this neglected tropical disease the better. I would argue the best way to achieve this is through cooperation rather than competition. As always, feedback is greatly appreciated.