AbstractIL‐13 is a central mediator of allergic inflammation and secreted by Th2 and bronchial smooth muscle cells (BSMC). However, little is known about the regulation of IL‐13 secretion. To address it, a cDNA library of BSMC was screened for the proteins interacted with IL‐13 by yeast two‐hybridization. Besides IL‐13 receptors, human sulfatase modifying factor 2 (SUMF2) was interacted with IL‐13. Furthermore, SUMF2 and IL‐13 were co‐immunoprecipitated from BSMC, which was independent of IL‐13 glycosylation. Interestingly, high levels of SUMF2 were expressed by BSMC, accompanied by significantly higher levels of intracellular IL‐13, but lower levels of IL‐13 secretion from BSMC. In contrast, little of SUMF2 was detected in lymphocytes, accompanied by lower levels of intracellular IL‐13, but significantly higher levels of 12 kDa form of IL‐13 secretion. Moreover, knockdown of SUMF2 expression by transfection with SUMF2‐specific siRNA did not alter IL‐13 mRNA transcription, but significantly reduced intracellular IL‐13 levels, associated with increased levels of IL‐13 secretion from BSMC. While induction of transient SUMF2 expression in lymphocytes failed to modulate IL‐13 mRNA transcription. It significantly increased the contents of 12 kDa form of intracellular IL‐13, accompanied by significantly reduced levels of IL‐13 in their supernatants. In addition, blockage of N‐glycosylation by treatment with tunicamycin eliminated 17 kDa form of intracellular IL‐13, but failed to promote IL‐13 secretion in BSMC. Collectively, our novel data clearly indicated that SUMF2 interacted with IL‐13 and inhibited IL‐13 secretion in BSMC and lymphocytes, which was independent of IL‐13 glycosylation. J. Cell. Biochem. 108: 1076–1083, 2009. © 2009 Wiley‐Liss, Inc.