Reciprocal regulation of iNOS and PARP-1 during allergen-induced eosinophilia

¹ Dept of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center
² Dept of Physiology, Tulane University Medical Center, New Orleans, LA 70112

^* To whom correspondence should be addressed. E-mail: hboulr{at}lsuhsc.edu.

	Abstract

iNOS inhibition was recently shown to exert no effect on allergen-challenge in human asthma, raising serious concerns about the role of the protein in the disease. Aim: We investigated the role of iNOS in ovalbumin-induced eosinophilia from the perspective of its relationship with poly(ADP-ribose) polymerase-1 (PARP-1) and oxidative DNA damage.

A mouse model of ovalbumin-induced eosinophilia was used to conduct the studies.

iNOS-associated protein nitration and tissue damage were partially responsible for allergen-induced eosinophilia. iNOS expression was required for oxidative DNA damage and PARP-1 activation upon allergen challenge. PARP-1 was required for iNOS expression and protein nitration, and this requirement was connected to NF-B. PARP-1 was an important substrate for iNOS-associated byproducts after ovalbumin-challenge. PARP-1 nitration blocked its poly(ADP-ribosyl)ation activity. IL-5-reestablishment in ovalbumin-exposed PARP-1^/ mice reversed eosinophilia and partial mucus production without a reversal of iNOS expression, concomitant protein nitration, or associated DNA damage.

Our results demonstrate a reciprocal relationship between iNOS and PARP-1 and suggest that expression of iNOS may be dispensable for eosinophilia after IL-5 production. iNOS may be required for oxidative DNA damage and full manifestation of mucus production. Such dispensability may explain, in part, the reported ineffectiveness of iNOS inhibition in preventing allergen-induced inflammation in humans.