The fundamental basis of inflammatory bowel disease

[Guest guest]

J. Clin. Invest. 117: 514-521 (2007).

The fundamental basis of inflammatory bowel disease

Warren Strober, Ivan Fuss and Mannon

http://www.jci.org/cgi/content/full/117/3/514

This paper argues that mutations like the NOD2/CARD15 gene mutation

found in Crohn's disease leads to " increased activation of NF-kB " ,

which then triggers proinflammatory cytokine production ... increased

levels of interleukin-12 and interleukin-23 in particular ... leading

eventually to the differentiation of T cells producing interferon-gamma

and interleukin-17, the proinflammatory cytokines responsible for

Crohn's disease.

How can this scheme be reconciled with the inhibition of activation of

NF-kB causing inflammatory bowel disease?

Dave

[Guest guest]

,

I noticed in the Nenci paper that they also discussed a knockout of

IKK2alpha that reduced but didn't block NFkB function. This partial

downregulation of NFkB did not lead to spontaneous colitis. Only when

NFkB was completely blocked by either NEMO (aka IKKgamma) or a

combination of IKK1alpha and IKK2alpha knockouts did they see the

colitis.I think all of their knockouts were conditional, under the

villin promoter so they are only knocked out in the colon epithelium,

not the immune system. It seems like some low level of NFkB signal is

required to prevent the colonic epithelial cells from being killed by

TNFalpha signaling that is elicited by bacterial growth. It seems like

a total lack of NFkB activity is probably not what most with colitis

have (because we wouldn't be able to keep our colons for years and

years), so I wonder how relevant a model this really is?

The BMJ paper you referred to distinguished between NFkB activation in

the colonic mucosa and in the macrophages. So maybe you need NFkB in

the colonic epithelia for them to survive, but if it is overly active

in the macrophages you get colitis? The papers you mention use biopsy

materials and mash them up to do Western blots. If macrophages are

infiltrating the biopsy, you would see higher NF-kB activity. In the

NEMO knockout, they isolate the epithelial cells and activate them

with LPS to see the response. So would there be any macrophages in

those samples in the Nenci paper? Maybe that's the answer to the paradox?

Martha

UC, 1979, PSC, 1992

> How can this scheme be reconciled with the inhibition of activation of

> NF-kB causing inflammatory bowel disease?

>

> Dave

>

[Guest guest]

Thank you Martha! Excellent suggestions!

Best regards,

Dave R.