628996290

HO-1 INHIBITSDC FUNCTION 1701

BLOOD. 1 SEPTEMBER 2005 • VOLUME 106. NUMBER 5

decrease T-cell proliferation and production of IFN-7 in MLRs. whereas expression of IL-10 was increased. IL-IO has been shown to błock MLRs and is considered as the main cytokine for the induction and maintenance of anergy or tolerance.^40-4S-4‘^J Moreover. IL-IO expressioti in MLRs is linkedto thegeneration ofTrl cells.⁵⁰ Further work is in progress to determine whether IL-10 acts downstream of HO-1. mediating suppression of DC’ maturation and possibly induction of tolerance. Altematively, the inhibition of MLRs could also be related to the heme degradation end product CO. because CO was shown to inhibit T-lymphocyte proliferation.⁵¹ These results indicate that HO-1 is not only a marker of iDCs but could also affect DC’ functions by inhibiting Th 1 responses and by inducing T-cell anergy. It is tempting to hypotli-esi/.e that the beneficial effect of HO-1 overexpression in autoim-mune disease.⁵² allotransplantation,⁶-⁵³ and graft-versus-host dis-ease'⁴ (GVHD) may be associated with the ability of HO-1 to błock DC maturation or inhibit Th 1 responses and induce T-cell anergy.

In agreement with the known antioxidant properties of HO-1 (for a review. see Otterbein and Choi¹). induction of HO-1 resulted in decreased ROS levels following LPS stimulation of DCs. Because ROS levels are inversely correlated to the degree of DC maturation⁵⁵ and because antioxidants błock DC maturation.³² the decrease in ROS levels by HO-1 could be involved in the inhibition of DC’ maturation. There are multiple downstream targets of ROS

References _ that will need to be analyzed to explain the inhibitory action of HO-1 on DC' maturation. Although S11PP further increased ROS levels in LPS-treated cells. it is possible that the DC maturation process is fully activated by the levels reached with LPS alone.

In conclusion. we demonstrate, for the first tiine. that luiman and rat iDCs express HO-1 and that HO-1 expression is strongly down-regulated duiing DC maturation. thus suggesting apotential role for HO-1 in DC biology. We present evidence that induction of HO-1 expression not only suppressed tlie expression of celi surface molecules and proinflammatory cytokines but. importantly. main-tained the expression of IL-10. This implies that HO-1 could selectively induce tolerogenic DCs.

The physiologic relevance of the present in vitro findings is strongly suppoited by the fact that mice lacking functional HO-1⁵⁶ and one human who had HO-1 deficiency⁵⁷-⁵⁸ have been associated with an inflammatory phenotype. and by results showing that overexpression of HO-1 inhibits allogeneic immune responses.⁵"

Acknowledgments

We are grateful to all of the researchers who kindly contributed with reagents or tissues.

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