An understanding of the pathological inflammatory mechanisms involved in SARS-CoV-2 virus infection is necessary in order to discover new molecular pharmacological targets for SARS-CoV-2 cytokine storm . In this study, the effects of a recombinant SARS-CoV-2 spike glycoprotein S1 was investigated in human peripheral blood mononuclear cells (PBMCs). Stimulation of PBMCs with spike glycoprotein S1 (100 ng/mL) resulted in significant elevation in the production of TNF & #945;, IL-6, IL-1ß and IL-8 . However, pre-treatment with dexamethasone (100 nM) caused significant reduction in the release of these cytokines . Further experiments revealed that S1 stimulation of PBMCs increased phosphorylation of NF- & #954; B p65 and I & #954; B & #945;, and I & #954; B & #945; degradation . DNA binding of NF- & #954; B p65 was also significantly increased following stimulation with spike glycoprotein S1 . Treatment of PBMCs with dexamethasone (100 nM) or BAY11-7082 (1 µM) resulted in inhibition of spike glycoprotein S1-induced NF- & #954; B activation . Activation of p38 MAPK by S1 was blocked in the presence of dexamethasone and SKF 86002 . CRID3, but not dexamethasone pre-treatment, produced significant inhibition of S1-induced activation of NLRP3/caspase-1 . Further experiments revealed that S1-induced increase in the production of TNF & #945;, IL-6, IL-1ß and IL-8 was reduced in the presence of BAY11-7082 and SKF 86002, while CRID3 pre-treatment resulted in the reduction of IL-1ß production . These results suggest that SARS-CoV-2 spike glycoprotein S1 stimulated PBMCs to release pro-inflammatory cytokines through mechanisms involving activation of NF- & #954; B, p38 MAPK and NLRP3 inflammasome . It is proposed that the clinical benefits of dexamethasone in COVID-19 are possibly due to its anti-inflammatory activity in reducing SARS-CoV-2 cytokine storm.