Posted by: Issa Abu-Dayyeh
The exact role played by the protein tyrosine phosphatase (SHP-1) in the negative regulation of macrophage functions has been an active area of research for many years. In fact, SHP-1 deficient mice are hyper-inflammatory. They lose their hair “for God’s sake” due to exaggerated inflammatory responses in the skin area! (hence their name motheaten). But what does this tell us? It tells us a lot of pathways are simply “on fire”. To dissect every single pathway controlled by this PTP is a humongous job, and the best approach in my opinion is to try to focus, and dissect a pathway at a time and a function at a time. So, what did we attempt to do in our most recent publication (Blanchette, J. et al.) in Immunology (2008)?
The paper explores the signaling pathways that seem to be major contributors to NO production in SHP-1 deficient macrophages. NO production is driven by a gene known as iNOS whose expression is driven by several transcription factors, most importantly: Nf-kB, STAT, and AP-1. One of those transcription factors “AP-1” is activated by a MAP kinase called JNK.
This work utilizes inhibitors of many of these members to see which of them will be able to suppress that excess NO production observed in SHP-1 deficient macrophages in an effort to understand how SHP-1 causes this increased NO production.
To save you the dull experimental details…Results showed that the exaggerated NO production in SHP-1-/- macrophages seems to be due to an increased JNK/AP-1 and not NF-kB activity.
And so what? some people might ask!
Well…I agree a finding like this might not find a cure to leishmaniasis. Nevertheless, bearing in mind that NF-kB translocation is increased in the absence of SHP-1, this paper then suggests something rather important. This increased NF-kB activity is not contributing to iNOS transcription. What is it doing then? and how can iNOS be differentially regulated? These are questions that await answers. (If somebody has answers, I will be glad to hear from them).
This work simply broadens our knowledge about where SHP-1 exerts its effects, and by knowing how, we can probably try to eventually revert some of those actions during the course of a Leishmania infection and help find an effective drug against leishmaniasis that is not as toxic as the ones available nowadays…
A block added to the wall. that is how I see it.
If you are interested in viewing the paper, please visit it here