Atopic dermatitis/eczema (AD) is a prototypic allergic disease characterized by pruritus and skin inflammation, and is often concomitant with other allergic disease (asthma, allergic rhinitis) through the immune phenomenon of atopic march. Interleukin-4 (IL-4), a Th2 cytokine, plays a key role in the pathogenesis of allergic disease. AD is also known to exhibit up-regulation of phosphodiesterase-4 (PDE4). Samrao et al. demonstrated that an oral PDE4 inhibitor, apremilast, improved disease severity scores in moderate-to-severe AD patients, including reducing itch and inflammation. We investigated whether apremilast can reverse IL-4-induced dysregulation of AD-related genes in keratinocytes. Primary human keratinocytes were treated for 24-hours with 10 ng/ml IL-4 alone, 1.25µM apremilast and IL-4 combined, or vehicle. Using reverse-transcription PCR method, several genes’ mRNA levels were measured. We found the IL-31 gene, associated with pruritus, was significantly up-regulated by IL-4 (p<0.05); this up-regulation was reversed by apremilast. To further our understanding of the molecular basis of apremilast activity, an inflammatory response PCR-array was used assessing differential gene expression potentially regulated by IL-4 and apremilast. We found 51 genes in total were regulated by IL-4. Of these, 28 genes were significantly (p<0.05) up-regulated at least 2-fold by IL-4, including CCL2, 3, 5, 24 and 26, CD74, CXCL 6, 9, 10 and 16, IL1A, IL5, IL12B, IL13RA2, IL19, IL20, IL25, IL27, IL31RA, LIF, NOS2, OSMR, and TNF. The remaining 23 genes were significantly (p<0.05) down-regulated at least 2-fold by IL-4, including CCL 17, 27, and 28, CXCL11 and 14, IFNE, INFK, IL1RN, LTB ,S100A8, TLR1, and TNFSF. The addition of apremilast either partially or fully normalized the expressions of 47 of the 51 genes induced or suppressed by IL-4. These data offer cellular evidence that the effects of IL-4 on keratinocytes are largely reversed by apremilast, providing molecular basis for the treatment of AD with apremilast. These data also suggest that apremilast could be useful for asthma or allergic rhinitis; further investigation is warranted.