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More MS news articles for November 2002

I{kappa}B kinase 2 but not NF-{kappa}B-inducing kinase is essential for effective DC antigen presentation in the allogeneic mixed lymphocyte reaction

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12393548&dopt=Abstract

Blood 2002 Sep 19
Andreakos E, Smith C, Monaco C, Brennan FM, Foxwell BM, Feldmann M.

Although dendritic cells (DC) are the most potent antigen-presenting cells involved in numerous physiological and pathological processes, little is known about the signaling pathways that regulate DC activation and antigen-presenting function.

Recently, we demonstrated that NF-kappaB activation is central to that process as overexpression of IkappaBalpha blocks the allogeneic mixed lymphocyte reaction (MLR), an in vitro model of T cell activation.

In this study, we investigated the role of two putative NF-kappaB inducing components, NF-kappaB-inducing kinase (NIK) and IkappaB kinase 2 (IKK2).

Using an adenoviral gene transfer method to efficiently express dominant negative (dn) forms of these molecules in monocyte-derived DC, we found that IKK2dn but not NIKdn inhibited the allogeneic MLR.

When DC were fixed, this inhibitory effect of IKK2dn was lost suggesting that IKK2 is involved in T cell-derived signals that enhance DC antigen presentation during the allogeneic MLR period rather than an effect on viability or differentiation state of DC prior to coculture with T cells.

One such signal is likely to be CD40 ligand (CD40L) as IKK2dn blocked CD40L but not LPS-induced NF-kappaB activation, cytokine production and up-regulation of costimulatory molecules and HLA-DR in DC.

In summary, our results demonstrate that IKK2 is essential for DC activation induced by CD40L or contact with allogeneic T cells, but not by LPS, whereas NIK is not required for any of these signals.

In addition, our results support IKK2 as a potential therapeutic target for the down-regulation of unwanted immune responses that may occur during transplantation or autoimmunity.