Ah, thanks. I assumed tapinarof was an inhibitor, as the papers on its mechanism describe it as downregulating cytokines. It appears the exact mechanism isn't quite clear. Bissonette et al 2021 [1]:
Tapinarof was found to bind directly to AhR, resulting in
downregulation of inflammatory cytokines, regulation of
skin barrier protein expression, and antioxidant activity
... In a T-cell polarization assay, tapinarof markedly
inhibited T-cell expansion and Th17-cell differentiation
and reduced the production of IL-17, while also reducing
IL-17A and IL17F levels in a CD4 T-cell assay.
It looks like tapinarof modulates the signaling behaviour of AhR, but so far the precise mechanisms are educated guesses.
The story of tapinarof's discovery is fascinating. It's produced by a bioluminescent (!) bacillus P. luminescens that (quoting from the paper) "lives symbiotically within parasitic, soil-living entomopathogenic nematodes." It was observed in the 1950s that "the nematode did not putrefy once dead, in contrast to the rapid decay seen in the absence of the nematode," leading to the idea that the bacillus' metabolites had antimicrobial activity — which turned out to include what is now synthesized as tapinarof.
Coal tar is another semi-natural substance that is thought to act on AhR.
And, yeah, good point re coal tar. AhR was once thought to be a toxin or junk receptor that activated liver enzymes for clearance of environmental waste and other chemical byproducts. The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) were, at one time, thought to be very similar. That might still be the case with respect to PXR and CAR, but I'm thinking that the way to bet is that there's more to them than was once thought...
The story of tapinarof's discovery is fascinating. It's produced by a bioluminescent (!) bacillus P. luminescens that (quoting from the paper) "lives symbiotically within parasitic, soil-living entomopathogenic nematodes." It was observed in the 1950s that "the nematode did not putrefy once dead, in contrast to the rapid decay seen in the absence of the nematode," leading to the idea that the bacillus' metabolites had antimicrobial activity — which turned out to include what is now synthesized as tapinarof.
Coal tar is another semi-natural substance that is thought to act on AhR.
[1] https://www.jaad.org/action/showPdf?pii=S0190-9622%2820%2932...