TNF- α/anti-TNF- α drugs and its effect on pregnancy outcomes

Abstract

Pregnancy is a complex biological process. The establishment and maintenance of foetal-maternal interface are pivotal events. Decidual immune cells and inflammatory cytokines play indispensable roles in the foetal-maternal interface. The disfunction of decidual immune cells leads to adverse pregnancy outcome. Tumour necrosis factor (TNF)-α, a common inflammatory cytokine, has critical roles in different stages of normal pregnancy process. However, the relationship between the disorder of TNF-α and adverse pregnancy outcomes, including preeclampsia (PE), intrauterine growth restriction (IUGR), spontaneous abortion (SA), preterm birth and so on, is still indefinite. In this review, we thoroughly reviewed the effect of TNF-α disorder on pathological conditions. Moreover, we summarized the reports about the adverse pregnancy outcomes (PE, IUGR, SA and preterm birth) of using anti-TNF-α drugs (infliximab, etanercept and adalimumab, certolizumab and golimumab) currently in the clinical studies. Overall, IUGR, SA and preterm birth are the most common adverse pregnancy outcomes of anti-TNF-α drugs. Our review may provide insight for the immunological treatment of pregnancy-related complication, and help practitioners make informed decisions based on the current evidences.

Keywords: Adverse pregnancy outcomes; TNF-α; TNF-α receptor; anti-TNF-α drugs.

Fig. 1.

TNF-R1-dependent signalling: once TNF-R1 binds mTNF-α or sTNF-α, it recruits the adaptor protein TRADD or FFADD via its DD motifs. Subsequently, it recruits complex I, namely serine/threonine kinase receptor interacting protein-1 (RIP-1), TNF-R-associated factor 2 (TRAF-2), as well as cIAP1 and cIAP2. Then, it activates NF-κB and JNK/AP1 signalling pathways and medicates the expression of targeted genes, finally involves in various biological processes, inducing inflammation, tissue degeneration, host defence, cell proliferation, cell survival and immunity. Besides, TRADD can also recruit and form the complex II (FADD, RIP-A, TRAF-2 and caspase 8) to finally activate caspase 3 eliciting cell apoptosis (Ref. 2). TNF-R2-dependent signalling: TNF-R2 is restricted to bind with mTNF-α, primarily recruiting TRAF-2 via its TRAF domain, which further causes the recruitment of complex II and activation of apoptosis, inflammation and necroptosis.